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Contemporary Cardiology
Series Editor: Peter P. Toth

Michael J. Wilkinson
Michael S. Garshick
Pam R. Taub Editors

Prevention
and Treatment
of Cardiovascular
Disease
Nutritional and Dietary Approaches
Contemporary Cardiology
Series Editor:
Peter P. Toth
Ciccarone Center for the Prevention of Cardiovascular Disease
Johns Hopkins University School of Medicine
Baltimore, MD
USA
For more than a decade, cardiologists have relied on the Contemporary
Cardiology series to provide them with forefront medical references on all
aspects of cardiology. Each title is carefully crafted by world-renown
cardiologists who comprehensively cover the most important topics in this
rapidly advancing field. With more than 75 titles in print covering everything
from diabetes and cardiovascular disease to the management of acute
coronary syndromes, the Contemporary Cardiology series has become the
leading reference source for the practice of cardiac care.

More information about this series at http://www.springer.com/series/7677

Michael J. Wilkinson
Michael S. Garshick • Pam R. Taub
Editors

Prevention
and Treatment
of Cardiovascular
Disease
Nutritional and Dietary Approaches
Editors
Michael J. Wilkinson Michael S. Garshick
Division of Cardiovascular Center for the Prevention of
Medicine, Department of Medicine Cardiovascular Disease and
University of California San Diego Leon H. Charney Division of
San Diego, CA Cardiology, Department of Medicine
USA New York University Langone Health
New York, NY
Pam R. Taub USA
Division of Cardiovascular
Medicine, Department of Medicine
University of California San Diego
San Diego, CA
USA

ISSN 2196-8969     ISSN 2196-8977 (electronic)

Contemporary Cardiology
ISBN 978-3-030-78176-7    ISBN 978-3-030-78177-4 (eBook)
https://doi.org/10.1007/978-3-030-78177-4

© Springer Nature Switzerland AG 2021

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Contents

1 Role of Dietary Nutrition, Vitamins, Nutrients,

and Supplements in Cardiovascular Health����������������������������������   1
Ryan Moran, Marsha-Gail Davis, and Anastasia Maletz
2 Impact of Nutrition on Biomarkers
of Cardiovascular Health���������������������������������������������������������������� 29
Cameron K. Ormiston, Rebecca Ocher, and Pam R. Taub
3 The Mediterranean Dietary Pattern���������������������������������������������� 47
Jessica K. Bjorklund, Carol F. Kirkpatrick,
and Eugenia Gianos
4 Dietary Approaches to Hypertension: Dietary Sodium
and the DASH Diet for Cardiovascular Health���������������������������� 61
Keith C. Ferdinand, Samar A. Nasser, Daphne P. Ferdinand,
and Rachel M. Bond
5 The Impact of Carbohydrate Restriction and Nutritional
Ketosis on Cardiovascular Health�������������������������������������������������� 73
Dylan Lowe, Kevin C. Corbit, and Ethan J. Weiss
6 Plant-Based Diets in the Prevention and Treatment of
Cardiovascular Disease������������������������������������������������������������������� 95
Rajiv S. Vasudevan, Ashley Rosander, Aryana Pazargadi,
and Michael J. Wilkinson
7 Plant-Based Oils ������������������������������������������������������������������������������ 115
Katrina Han, Kelley Jo Willams, and Anne Carol Goldberg
8 Prevention and Treatment of Obesity for Cardiovascular
Risk Mitigation: Dietary and Pharmacologic Approaches���������� 129
Joanne Bruno, David Carruthers, and José O. Alemán
9 Fasting for Cardiovascular Health ������������������������������������������������ 143
Elizabeth S. Epstein, Kathryn Maysent,
and Michael J. Wilkinson

v
vi Contents

10 Optimal Dietary Approaches for Those Living

with Metabolic Syndrome to Prevent Progression
to Diabetes and Reduce the Risk of Cardiovascular Disease ������ 161
Melroy S. D’Souza, Tiffany A. Dong, Devinder S. Dhindsa,
Anurag Mehta, and Laurence S. Sperling
11 Optimal Diet for Diabetes: Glucose Control,
Hemoglobin A1c Reduction, and CV Risk������������������������������������ 171
Wahida Karmally and Ira J. Goldberg
12 Dietary and Lifestyle Cardiometabolic Risk Reduction
Strategies in Pro-inflammatory Diseases �������������������������������������� 179
Ashira Blazer, Kinjan Parikh, David I. Fudman,
and Michael S. Garshick
13 Dietary Approaches to Lowering LDL-C�������������������������������������� 193
Parag Anilkumar Chevli and Michael D. Shapiro
14 Lifestyle Approaches to Lowering Triglycerides�������������������������� 211
Stephen J. Hankinson, Michael Miller,
and Andrew M. Freeman
15 Role of the Microbiome in Cardiovascular Disease���������������������� 225
Thanat Chaikijurajai, Jennifer Wilcox,
and W. H. Wilson Tang
16 Dietary and Nutritional Recommendations
for the Prevention and Treatment of Heart Failure���������������������� 251
Prerana Bhatia and Nicholas Wettersten
17 Dietary Considerations for the Prevention
and Treatment of Arrhythmia�������������������������������������������������������� 265
Marin Nishimura and Jonathan C. Hsu

Index���������������������������������������������������������������������������������������������������������� 273
Contributors

José O. Alemán Division of Endocrinology, Department of Medicine, New

York University Langone Health, New York, NY, USA
Prerana Bhatia Division of Cardiology, University of California, San
Diego, La Jolla, CA, USA
Jessica K. Bjorklund North Shore University Hospital, Manhasset, NY,
USA
Zucker School of Medicine, Hempstead, NY, USA
Ashira Blazer Division of Rheumatology, Department of Medicine, New
York University Langone Health, New York, NY, USA
Rachel M. Bond Dignity Health, Chandler Regional Medical Center,
Chandler, AZ, USA
Creighton University School of Medicine, Omaha, NE, USA
Joanne Bruno Division of Endocrinology, Department of Medicine, New
York University Langone Health, New York, NY, USA
David Carruthers Division of Endocrinology, Department of Medicine,
New York University Langone Health, New York, NY, USA
Thanat Chaikijurajai Department of Cardiovascular Medicine, Heart,
Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH, USA
Department of Internal Medicine, Faculty of Medicine Ramathibodi Hospital,
Mahidol University, Bangkok, Thailand
Parag Anilkumar Chevli Center for Prevention of Cardiovascular Disease,
Section on Cardiovascular Medicine, Wake Forest University Baptist Medical
Center, Medical Center Boulevard, Winston Salem, NC, USA
Kevin C. Corbit The Cardiovascular Research Institute, University of
California, San Francisco, CA, USA
Marsha-Gail Davis Department of Family Medicine, UCSD/SDSU
Preventive Medicine Residency, University of California, San Diego Health,
San Diego, CA, USA
San Diego State University School of Public Health, San Diego, CA, USA

vii
viii Contributors

Devinder S. Dhindsa Emory Clinical Cardiovascular Research Institute,

Division of Cardiology, Emory University School of Medicine, Atlanta, GA,
USA
Tiffany A. Dong Department of Internal Medicine, Emory University
School of Medicine, Atlanta, GA, USA
Melroy S. D’Souza Department of Internal Medicine, Emory University
School of Medicine, Atlanta, GA, USA
Elizabeth S. Epstein Division of Cardiovascular Medicine, Department of
Medicine, University of California San Diego, San Diego, CA, USA
Keith C. Ferdinand Gerald S. Berenson Endowed Chair in Preventive
Cardiology, Tulane University School of Medicine, New Orleans, LA, USA
Daphne P. Ferdinand Healthy Heart Community Prevention Project, Inc,
New Orleans, LA, USA
Andrew M. Freeman Division of Cardiology, Department of Medicine,
National Jewish Health, Denver, CO, USA
David I. Fudman Division of Digestive and Liver Diseases, Department of
Medicine, University of Texas Southwestern Medical Center, Dallas, TX,
USA
Michael S. Garshick Leon H. Charney Division of Cardiology, Department
of Medicine, New York University Langone Health, New York, NY, USA
Center for the Prevention of Cardiovascular Disease, New York University
Langone Health, New York, NY, USA
Eugenia Gianos Zucker School of Medicine, Hempstead, NY, USA
Cardiovascular Prevention, Northwell Health, New Hyde Park, NY, USA
Western Region, Katz Institute Women’s Heart Program, Manhasset, NY,
USA
Women’s Heart Program, Lenox Hill Hospital, New York, NY, USA
Ira J. Goldberg Division of Endocrinology, Diabetes and Metabolism,
New York University Grossman School of Medicine, New York, NY, USA
Stephen J. Hankinson Division of Cardiology, Department of Medicine,
University of Maryland School of Medicine, Baltimore, MD, USA
Jonathan C. Hsu Cardiac Electrophysiology Section, Division of
Cardiology, Department of Medicine, University of California, San Diego,
La Jolla, CA, USA
Wahida Karmally Columbia University, New York, NY, USA
Carol F. Kirkpatrick Idaho State University Wellness Center, Pocatello, ID,
USA
Dylan Lowe The Cardiovascular Research Institute, University of California,
San Francisco, CA, USA
Contributors ix

Anastasia Maletz Department of Family Medicine, UCSD/SDSU Preventive

Medicine Residency, University of California, San Diego Health, San Diego,
CA, USA
San Diego State University School of Public Health, San Diego, CA, USA
Kathryn Maysent Division of Cardiovascular Medicine, Department of
Medicine, University of California San Diego, San Diego, CA, USA
Anurag Mehta Emory Clinical Cardiovascular Research Institute, Division
of Cardiology, Emory University School of Medicine, Atlanta, GA, USA
Michael Miller Division of Cardiology, Department of Medicine, University
of Maryland School of Medicine, Baltimore, MD, USA
Ryan Moran Department of Medicine, University of California, San Diego
Health, San Diego, CA, USA
Department of Family Medicine, UCSD/SDSU Preventive Medicine
Residency, University of California, San Diego Health, San Diego, CA, USA
San Diego State University School of Public Health, San Diego, CA, USA
Samar A. Nasser Department of Clinical Research & Leadership, School of
Medicine and Health Sciences, The George Washington University,
Washington, DC, USA
Marin Nishimura Cardiac Electrophysiology Section, Division of
Cardiology, Department of Medicine, University of California, San Diego,
La Jolla, CA, USA
Rebecca Ocher Department of Medicine, University of California, Los
Angeles, Los Angeles, CA, USA
Cameron K. Ormiston Division of Cardiovascular Diseases, Department of
Medicine, University of California, San Diego, La Jolla, CA, USA
Kinjan Parikh Leon H. Charney Division of Cardiology, Department of
Medicine, New York University Langone Health, New York, NY, USA
Aryana Pazargadi Division of Cardiovascular Medicine, Department of
Medicine, University of California San Diego, San Diego, CA, USA
Ashley Rosander Division of Cardiovascular Medicine, Department of
Medicine, University of California San Diego, San Diego, CA, USA
Michael D. Shapiro Center for Prevention of Cardiovascular Disease,
Section on Cardiovascular Medicine, Wake Forest University Baptist Medical
Center, Medical Center Boulevard, Winston Salem, NC, USA
Laurence S. Sperling Emory Clinical Cardiovascular Research Institute,
Division of Cardiology, Emory University School of Medicine, Atlanta, GA,
USA
W. H. Wilson Tang Department of Cardiovascular Medicine, Heart, Vascular
and Thoracic Institute, Cleveland Clinic, Cleveland, OH, USA
x Contributors

Center for Microbiome and Human Health, Department of Cardiovascular

and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic,
Cleveland, OH, USA
Pam R. Taub Division of Cardiovascular Medicine, Department of
Medicine, University of California San Diego, San Diego, CA, USA
Rajiv S. Vasudevan University of California, San Diego School of Medicine,
La Jolla, CA, USA
Ethan J. Weiss The Cardiovascular Research Institute, University of
California, San Francisco, CA, USA
Nicholas Wettersten Division of Cardiology, University of California, San
Diego, La Jolla, CA, USA
Section of Cardiology, San Diego Veterans Affairs Health System, San Diego,
CA, USA
Jennifer Wilcox Center for Microbiome and Human Health, Department of
Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland
Clinic, Cleveland, OH, USA
Michael J. Wilkinson Division of Cardiovascular Medicine, Department of
Medicine, University of California San Diego, San Diego, CA, USA
 Role of Dietary Nutrition,
Vitamins, Nutrients,
1
and Supplements
in Cardiovascular Health

Ryan Moran, Marsha-Gail Davis,

and Anastasia Maletz

Regular supplement use has increased in the last include multivitamins (MVI)—which include
several decades in USA, with now almost 50% both varied and single vitamin formulations—
of Americans reporting regular use. The primary mineral and elemental formulated supplements,
reason or motivator for use of dietary supple- and macronutrient compounds which have physi-
ments is to improve, supplement, or maintain ologic roles in pathways related to metabolism
health [1]. However, despite this, there remains and homeostasis.
uncertainty and misunderstanding regarding
many of these supplements and their role in car-
diovascular protection, namely because of the Multivitamin and B Vitamins
intense heterogeneity, availability, and dose vari-
ations of supplements. Because of the prevalence MVI and water-soluble vitamin supplementa-
and interest in use, there has been a great interest tion has been a subject of interest for decades
in better understanding how micro- and macro- for cardiovascular disease (CVD) treatment or
nutrients mitigate disease and potentiate health. prevention, owing in part to the role of inflam-
Some of the most widely used supplements mation in the development of heart disease.
Epidemiological studies have noted inverse
relationships between diets high in vegetables,
R. Moran (*) fruits, and whole grains and incident heart dis-
Department of Medicine, University of California, ease, and augmenting diets with substrates of
San Diego Health, San Diego, CA, USA these diets have been reasoned to have a role
Department of Family Medicine, UCSD/SDSU in atherogenesis [2]. However, single-­pill MVI
Preventive Medicine Residency, University of supplements have been a challenge to study,
California, San Diego Health, San Diego, CA, USA
as well as to interpret across studies, owing to
San Diego State University School of Public Health, notable heterogeneity in inclusion constituents,
San Diego, CA, USA
e-mail: [email protected] doses, inclusion criteria, and endpoints. Despite
this, pervasive evidence has not found that sup-
M.-G. Davis · A. Maletz
Department of Family Medicine, UCSD/SDSU plementation of combined MVI provides benefit
Preventive Medicine Residency, University of for either primary or secondary cardiovascular
California, San Diego Health, San Diego, CA, USA prevention [3, 4]. In one large Euopean study,
San Diego State University School of Public Health, over 6000 healthy individuals were randomized
San Diego, CA, USA to a combination of 120 mg ascorbic acid, 30 mg
e-mail: [email protected];
of Vitamin E, 6 mg of β-carotene, 100 μg of sele-
[email protected]

© Springer Nature Switzerland AG 2021 1

M. J. Wilkinson et al. (eds.), Prevention and Treatment of Cardiovascular Disease, Contemporary
Cardiology, https://doi.org/10.1007/978-3-030-78177-4_1
2 R. Moran et al.

nium, and 20 mg of zinc for a median 7.89 years favorably alter both triglyceride and low-density
and found no cardiovascular benefit of supple- lipoprotein (LDL) levels modestly in low and
mentation [5]; more recently, a double-blinded moderate risk individuals [13]. Long-term and
study in USA evaluated that a combined MVI outcome data, however, are lacking, though it is
containing 32 different compounds in older men generally well tolerated and carries minimal risk.
found a trend toward less myocardial infarction Vitamin B3 (niacin, including nicotinamide
in those with established CVD at baseline, but and nicotinic acid) is metabolized to nicotinamide
no difference in the study’s primary or second- adenine dinucleotide (NAD) which is an impor-
ary endpoints, and no difference in outcomes for tant cofactor in enzymatic processes including
primary prevention [6]. in generation of adenosine triphosphate (ATP),
From a cardiovascular standpoint, three of nine a major cellular energy source. Supplementation
B vitamins have a role in homocysteine metabo- of nicotinic acid in high-dose augments lipid pro-
lism (pyroxidine (B6), cyanocobalamin (B12), and files favorably, including increasing HDL and
folate (B9)), and given the proposed role of homo- lowering LDL and triglycerides [14]. Outcome
cysteine in progression of atherogenesis, there has data, however, have been mixed: one random-
been considerable interest in evaluating supple- ized long-term (6.2 years) study using 3000 mg
mentation in higher risk individuals to prevent dis- daily found fewer non-fatal MI compared with
ease progression [4]. Empirical support includes placebo, but increased rates of pulmonary throm-
evidence that supplementing these three vitamins boembolic events and arrhythmia events [15].
can decrease surrogate markers of risk, such as In addition, the study adherence was lower and
serum homocysteine concentrations [7], and that B dropout rate higher in the niacin arm (compared
supplementation may be associated with decreas- with placebo or fibrate) owing to the side effects
ing carotid intima media thickness progression of niacin including flushing, gastrointestinal side
[8]. However, interventional trials have generally effects, and cardiovascular symptoms (includ-
failed to find support for routine supplementation ing palpitations, headaches, increased heart rate,
in average or high-risk individuals for cardiovas- and low blood pressure). Interestingly, long-term
cular benefit. While one large study supplement- (mean 15 years) follow-­up to this noted decreased
ing folate in middle aged Chinese hypertensive overall mortality rates in those in the niacin arm
individuals did show decreased composite cardio- compared with placebo, though the mechanisms
vascular events [9], this has not been consistently are not entirely clear but possibly related to the
found in other studies [10]. lipid profile benefits [16]. Several studies have
Vitamin B1 (thiamine) serves a variety of found little evidence to support added benefit
physiologic roles including as an essential cofac- in addition to statin therapy, however, but have
tor in lipid metabolism as thiamin diphosphate, found increased side-effect profiles (especially
and deficiencies have been noted more com- at pharmacologic doses) and concerns for possi-
monly in patients with heart failure. Supporting bly increased all-cause mortality [17–19]. Thus,
this association, some evidence has found sup- niacin is generally not recommended either for
plementation may have a role in left ventricular therapeutic benefit in secondary prevention, nor
function [11, 12], although the clinical meaning for primary prevention except in specific circum-
is still unclear as data on functional improvement stances such as intolerance to safer options.
are lacking and the absolute difference—while
significant—was relatively small.
Vitamin B5 (pantothenic acid) is metabolized Vitamin C
into pantethine which has direct and indirect
influences on lipid metabolism via inhibition Vitamin C (l-ascorbic acid) is an essential diet
of acetyl-coenzyme (CoA) carboxylase and component with a wide range of physiologic
3-hydroxy-3-methyl-glutaryl-CoA reductase. activities including in the synthesis of collagen
Supplementation in high doses has been found to and some hormones, as well as an established
1 Role of Dietary Nutrition, Vitamins, Nutrients, and Supplements in Cardiovascular Health 3

antioxidant and pro-oxidant. In addition, it has a pathway to becoming bioactive vitamin A. It is

role in monocyte vascular adhesion and is thought then esterified, incorporated into chylomicrons,
to have a role in atherogenesis. Deficiencies are secreted via lymphatic drainage, and eventually
rare but are associated with blood vessel fragility enter the bloodstream for storage (mainly in the
and the clinical manifestation of scurvy. Higher liver) or for cellular distribution [31]. Retinoic
intake of vitamin C has been noted to potenti- acid, the major bioactive form of vitamin A, acts
ate the antioxidant role of this compound, and in a paracrine or autocrine hormone, impact-
epidemiological support exists for an inverse ing cellular regulation, growth, and function.
association with intake and incident heart dis- Although unusual, deficiencies are usually asso-
ease [20–23]. Prospective studies however have ciated with vision deficiencies (e.g., night blind-
found mixed results: in post-menopausal women, ness), and immune and integumentary issues
supplementation—but not dietary intake—was [30]. However, epidemiologic support has asso-
associated with decreased incident CVD [24], ciated higher intake of carotenoid-rich diets with
but high-dose supplementation in men without lower CVD risk and low measured serum carot-
heart disease failed to find this and instead found enoids with increased risk of subsequent isch-
a trend toward higher cardiovascular mortality emic event risk [32]. Despite these associations,
[25]. A large pooled meta-analysis of prospective several clinical trials have thus far failed to pro-
studies found high diet intake—but not supple- vide conclusive evidence that supplementation of
ment intake—inversely associated with CVD vitamin A or provitamin A decreases CVD risk or
incidence [20]. Randomized trials have consis- decreases the risk in those with established heart
tently found little evidence that supplementation disease [33]; in contrast, some trials [33–35] have
of vitamin C is effective for either primary or raised concern for a possibly increased risk.
secondary prevention of adverse cardiac events Disagreement between epidemiological asso-
[26–28]. Therefore, a varied diet of fruits and ciations and clinical trial findings has not been
vegetables, including those containing high entirely elucidated. The diversity of dietary
amounts of vitamin C, are recommended rather carotenoids and confounding of a diet rich in
than supplementation for heart health, as little carotenoids—rather than carotenoids them-
evidence supports supplementation use to pre- selves—have been proposed [36, 37]. Given con-
vent heart disease [29]. cerns of potential harms (including lung cancer in
smokers or those with asbestos exposure, beyond
the scope of this review) in supplementation, rou-
Vitamin A tine recommendation for vitamin A or provitamin
A is not generally recommended for primary or
Vitamin A (retinol, retinal, and retinyl esters) secondary prevention of CVD [38].
is composed of a group of related hydrophobic
compounds which have numerous physiologic
roles and is consumed either as a provitamin A Vitamin D
carotenoid compound or complete vitamin A
compound which is then hydrolyzed in the intes- Vitamin D is predominantly obtained by syn-
tinal lumen to be absorbed [30]. Once ingested, thetic processes in the skin by ultraviolet B
provitamin A or its active homolog is incor- (UVB) from sunlight, and secondarily from
porated in the formation of bile acid micelles food sources. Once activated from 25(OH)D to
is solubilized and eventually is absorbed into 1,25-dihydroxyvitamin D (mostly in the kid-
enterocytes with dose- and concentration-­ neys), the hormone calcitriol plays important
independent mechanism, contributing to a poten- homeostatic functions in calcium regulation and
tial for toxicity. Provitamin A (most commonly acts on numerous different tissues throughout the
α-carotene, β-carotene, and β-cryptoxanthin) can body including the heart and vascular system,
be converted to retinol and enter the metabolic where vitamin D receptors are present [39, 40].
4 R. Moran et al.

Physiologically, calcitriol has been shown to stop was a secondary endpoint [47]. In addition, the
vascular smooth muscle cells from proliferating amount supplemented was generally considered
and have been theorized to contribute to calcium low (400 IU daily in two divided doses, with
deposition and arterial calcification. Further, low calcium). The ViDA study in New Zealand, in
calcitriol serum concentrations cause a homeo- contrast, randomized over 5000 individuals to
statically regulated increase in parathyroid hor- high-dose monthly (100,000 IU or more) vitamin
mone, which has been implicated in increasing D and found after over 3 years that compared
both vascular and myocardial calcification. with placebo, there was no effect on cardiovas-
Finally, low calcitriol has been shown to upregu- cular outcomes, including in the subgroup analy-
late pro-inflammatory cytokines (IL-6, TNF-a) sis of individuals with known CVD [48]. Finally,
and downregulate IL-10, and renin–angiotensin– more recently, the VITAL study randomized over
aldosterone system activation, further supporting 20,000 individuals to 2000 IU daily (see Omega-3
its role in heart disease risk. Epidemiological section) and found after a median follow-up of
support includes noted associations between over 5 years, there was similarly no benefit of
country latitude and cardiovascular death rates, supplementation on CVD in low-risk individu-
seasonality trends and increased incidence of als [49]. In both the ViDA and VITAL studies,
risk in the winter, and decreased rates in higher subgroup analysis similarly failed to show ben-
altitudes of residence, all suggesting the protec- efit in individuals with vitamin D deficiency at
tive role of UVB activation of vitamin D. Serum randomization.
levels of 25(OH)D have been noted inversely There still remains incredible interest given
associated with cardiovascular mortality [40, 41]. the physiological mechanisms and epidemiologi-
Additionally, the British Regional Heart Study cal findings, and many trials including higher risk
noted higher risk of ischemic heart disease in individuals are ongoing. However, currently there
men living in more northern locations over time, is insufficient evidence to recommend vitamin D
suggesting more than simple corollary evidence. for primary or secondary prevention of CVD.
In this study, while blood levels of vitamin D
were not assessed, and smoking rates were noted
higher in these locations as well, there was not Vitamin E
an association between blood pressure and smok-
ing rates, though blood pressure was noted higher Vitamin E (tocopherols and tocotrienols) is com-
in locations further north [42], perhaps explain- posed of eight isomeric molecules, functions as
ing some of the author’s findings as vitamin D an important antioxidant, protecting free radical
deficiency has been associated with increased damage to lipid-rich cellular environments such
risk of hypertension [43]. While studies have as those found in membranes and lipoproteins,
supported vitamin D supplementation with low- and helps to stabilize membrane structures. Once
ering C-reactive protein, evidence that supple- consumed, vitamin E is transported predomi-
mentation has a role in lowering blood pressure nantly by LDL and stored in fat-rich cellular
has been mixed, especially in healthy individuals structures throughout the body including the
[44–46]. kidney, liver, brain, and heart [50]. Deficiencies
Intervention studies regarding CVD and vita- of vitamin E are rare and are generally associ-
min D supplementation have been limited but ated with neurologic compromise [31]; however,
generally have not found positive results with their role as a potent antioxidant has been theo-
supplementation. The Woman’s Health Initiative rized to be important in cardiovascular protection
followed post-menopausal women (mean of and chronic disease progression, specifically by
7 years) and found no clear association between preventing oxidative stress and progression of
calcium and vitamin D compared with pla- atherosclerosis [51, 52]. Further, vitamin E has
cebo on cardiovascular outcomes, although this a role in decreasing platelet aggregation, throm-
1 Role of Dietary Nutrition, Vitamins, Nutrients, and Supplements in Cardiovascular Health 5

bosis formation, and monocyte activation [31, the anti-inflammatory properties of this vitamin
53]. Support for these claims comes from epide- [60–62]. However, given some heterogeneity of
miological studies associating a higher reported results in clinical trials, and because of appre-
intake of vitamin E and lower risk of atheroscle- hension of safety data balancing benefits and
rotic heart disease [54, 55]. Because of these harms (including possibly increased risk of pros-
associations, in the last 20 years, there has been tate cancer among those taking vitamin E [63]),
a tremendous interest in evaluating the effect of supplementation recommendations clinically are
vitamin E supplementation for both primary and generally made on a case-by-case basis. This is
secondary prevention of heart disease. similarly reflected in the USPSTF review and
While primary prevention studies have had guidance recommendation for vitamin E supple-
varied methods, generally they have failed to mentation in 2014 [38].
show conclusive evidence that regular sup-
plementation decreases incident myocardial
infarction or major adverse cardiac events. For Vitamin K
example, while nonsignificant trends have been
noted to favor vitamin E supplementation in both Vitamin K (in plants, phylloquinone (K1); mena-
the Alpha-Tocopherol Beta-Carotene Cancer quinone (K2), and menadione (K3) ultimately
Prevention Study and the Woman’s Health Study derived from K1) is an essential substrate for
[56], these trends were not supported by the physiologic enzymatic processes including con-
Physicians Health Study (PHI) evaluating healthy verting glutamyl residues to γ-carboxyglutamyl
men. Further, there was a statistically significant (Gla) residues. This action is important in bone
increase in risk of intracranial bleed in men in the homeostasis, the blood coagulation cascade,
PHI who received vitamin E [26]. as well as in activating matrix Gla proteins, or
In individuals with established CVD, vita- MGP. MGP is synthesized in smooth muscle cells,
min E has been supported by some, but not all and early investigations in animal studies have
clinical trials. An early study in evaluating 52 found it is an important inhibitor of calcification
patients after percutaneous transluminal angio- including in the coronary arteries [64]. Vitamin K
plasty found a nonstatistically significant trend has also been recognized as having anti-inflam-
toward less restenosis [57], and the CHAOS trial matory actions and suppresses NF-κB, possibly
in 1996 found less composite cardiovascular contributing to its role in preventing vascular cal-
death and nonfatal MI, though this was driven cification. While vitamin K deficiencies are rare,
by decreased nonfatal MI, and there was a trend in certain high-risk populations (such as those
toward increased total mortality in the interven- with kidney disease), and in those taking vitamin
tion arm. In contrast, the HOPE trial (4 years) K antagonist medications, there is epidemio-
and HOPE extension trial (median total 7-year logical association with markers of low vitamin
follow-up) found no benefit of vitamin E supple- K levels and increased cardiovascular mortality
mentation on major adverse cardiac events, and and/or vascular calcification [65]. Cohort studies
the extension trial noted an increase in heart fail- have found circulating phylloquinone levels to
ure incidence [58, 59]. not be associated with coronary artery calcifica-
Therefore, it remains uncertain if vitamin E tion (CAC) progression after over 2 years [66];
supplementation provides cardiovascular ben- in contrast, phylloquinone supplementation in
efit in low- or high-risk individuals, and existing healthy middle aged and older adults was found,
evidence refutes supporting routine recommen- after 3 years to decrease progression in CAC in a
dation for use in individuals. There has been subgroup analysis of those adherent to treatment,
recent suggestion of vitamin E having a role in but not stop new CAC formation [67]. K2 has
improving clinical indices noted in non-alcoholic been also subject of research interest, as it has a
steatohepatitis, thought driven at least in part by longer half-life, is considered more potent, and is
6 R. Moran et al.

the major storage form of vitamin K in humans underlying physiological abnormalities contrib-
[68]. K2 intake has been shown to decrease arte- uting to the development of CVD.
rial stiffness [69], and while cohort studies have
found that higher dietary consumption has been
associated with lower cardiovascular mortality Zinc
and aortic calcifications [70, 71], a large meta-
analysis only found trends in lower risk of heart Zinc is an essential mineral that supports nor-
disease and serum markers of vitamin K intake mal growth and development via several cellu-
[72]. More recently, a meta-analysis of US-based lar processes including protein synthesis, DNA
studies similarly failed to find differences in car- synthesis, cellular division, and cellular metabo-
diovascular outcomes [73]. lism [74]. It also serves as a catalyst and more
Several investigational studies are ongoing; specifically a cofactor in hundreds of enzymatic
there are no current randomized controlled tri- reactions and plays a role in immune function,
als (RCTs) evaluating vitamin K intake showing skin integrity, and wound healing as well as the
benefit for supplementation and cardiovascular olfactory system with proper taste and smell.
outcomes. As noted above, several markers of Supplemental forms of zinc include zinc acetate,
cardiovascular health have shown promise (such zinc gluconate, and zinc sulfate with the percent-
as CAC), and thus, these studies will likely pro- age of elemental zinc varying by form. Research
vide valuable insight; however, currently there is is not yet sufficient to provide clarity on the
uncertain benefit of supplementation. absorption, bioavailability, and tolerance of these
forms [75].
Zinc is absorbed by transcellular processes
 lemental Mineral Nutrient
E where the highest transport velocity rate occurs in
Supplements the jejunum of the small intestines. Zinc absorp-
tion appears to occur with a level of saturability
Elemental minerals are essential, meaning they and dynamic efficiency where transport veloc-
must be obtained from dietary sources as they are ity increases as zinc availability decreases. Zinc
not able to be synthesized by the body, and oper- concentrations in the blood are tightly regulated
ate as cofactors in multiple crucial physiological where levels can remain fairly stable at both low
processes. Many minerals exhibit a U-shaped and high levels of zinc functional stores. Of note,
curve as it pertains to their relationship with dis- the body requires daily zinc intake as there are no
ease, which mirror the homeostatic tendency of specialized zinc storage systems in the body as
the body to require a specific range for optimal observed with other minerals like calcium.
function. Adequate dietary intake appears to be Oxidative stress and inflammation are under-
linked inversely with CVD while use of supple- stood to be key underlying mechanisms in the
ments especially when internal levels are adequate pathophysiology of CVD, particularly athero-
may increase risk of CVD events and mortality. sclerosis [76]. Studies have shown an inverse
With this information, the best approach that can relationship between zinc deficiency and cellular
be recommended is to gain adequate nutrient oxidative stress [77, 78], where zinc deficiency
intake from dietary sources and supplements if a increases the production of reactive oxidative
deficiency is present. Supplementation outside of species [76]. Zinc also serves to regulate key
the need to optimize diet can promote inappropri- modulators, such as NF-κB, in inflammatory
ate use and the perpetuation of poor nutrition as response pathways, where zinc deficiency has
well as potentially increasing the risk of adverse been shown to increase the activation of NF-κB
health outcomes. Perturbations of these tightly and affect the production of cytokines [79].
regulated systems due to dietary inadequacy have Though the exact function of zinc ions in normal
widespread consequences, with dysregulation of cardiac physiology remains unknown, zinc status
mineral homeostasis seeming to be one of the changes, particularly zinc deficiency, have been
1 Role of Dietary Nutrition, Vitamins, Nutrients, and Supplements in Cardiovascular Health 7

reportedly linked to various CVDs [76], includ- that zinc consumed at abnormally high doses
ing hypertension [80], myocardial infarction [81], (142 mg/day) may decrease magnesium absorp-
atrial fibrillation, and congestive heart failure as tion [89]. Vitamin D has been linked to improved
well as metabolic syndrome [82]. Studies have magnesium absorption [74].
implicated zinc deficiency in the development Once consumed, magnesium is efficiently
of atherosclerosis and subsequent complications absorbed mainly in the jejunum and ileum [90]
of heart disease including MI and stroke [76]. and in smaller amounts in the colon [91]. Similar
Evidence from epidemiologic studies suggests to zinc and calcium, magnesium absorption is
that the progression of atherosclerosis is modi- inversely related to the magnesium availability in
fied by many nutritional factors including zinc. the diet, where the less magnesium is consumed,
However, this relationship has not been confirmed the more is absorbed. Magnesium absorption is
in randomized clinical trials assessing the role of facilitated via both unsaturable passive transport
zinc in primary prevention. Some studies have and unsaturable active transport mechanisms. As
also shown association between higher intake it relates to the heart, magnesium contributes to
of zinc and CVD [83], which may be attributed normal cardiovascular function by playing a role
to high meat consumption in Westernized diets. in the transport of calcium and potassium across
Many RCTs have typically used combination cell membranes and thus crucial to the mainte-
supplements that include zinc but do not provide nance of normal sinus rhythm [92].
zinc supplementation solely. Current evidence is In cardiac physiology, magnesium plays a key
not sufficient to support the use of supplementa- role in modulation neuronal excitation, intracar-
tion in primary prevention [84]. diac conduction, and myocardial contraction [93]
and helps to maintain electrical, metabolic, and
vascular homeostasis [94]. Magnesium depletion
Magnesium has significant effects on cardiovascular func-
tion [95] as well as neuromuscular function and
Following calcium, sodium, and potassium, mag- has been associated with CVD [94] risk factors
nesium is the fourth most common mineral in including hypertension [95], diabetes, dyslipid-
the human body [85]. Magnesium is an essential emia, atherosclerosis, and metabolic syndrome
nutrient and is abundant and naturally occurring [96] and ultimately even CVD [97]. This cor-
in many foods. It is crucial to vital processes relation between hypomagnesemia and CVD
occurring in the body such as those involved is also observed in CKD patients where CVD
with muscle and nerve function, apoptosis [86], mortality is higher [98]. Evidence from a vari-
regulation of blood glucose levels, blood pres- ety of studies including epidemiological stud-
sure [87], and bone formation as well as DNA ies, RCTs, and meta-analyses have suggested an
and protein synthesis [88]. Magnesium, like inverse relationship between magnesium intake
many other minerals, serves as a cofactor in hun- and CVD. Higher dietary magnesium intake was
dreds of enzymatic reactions, especially those associated with both lower CV risk factors and
involved with cellular metabolism (i.e., oxidative CVD-related mortality [99]. Magnesium supple-
phosphorylation and glycolysis [87]). In supple- mentation has been associated with favorable
mental forms, magnesium is available as magne- effects on CVD risk factors, including improve-
sium aspartate, magnesium chloride, magnesium ment in arterial stiffness, endothelial function
citrate, magnesium lactate, and magnesium [99], overall blood pressure [100], insulin resis-
oxide. Some studies suggest that magnesium is tance [101], and metabolic syndrome, but more
better absorbed and bioavailable in the aspartate, studies are needed to elucidate the role of supple-
chloride, citrate, and lactate forms compared to mentation in primary prevention [102]. In one
oxide and sulfate forms. It has also been found meta-analysis, a 100-mg increment in magnesium
8 R. Moran et al.

intake was associated with 5% risk reduction in interchangeable functions where they can occupy
hypertension [103]. Evidence of the differential activation sites in proteins requiring either Mg or
impact of one form compared to another has not Mn with similar efficiency. Some animal studies
been evaluated as yet in the research. have suggested that manganese supplementation
can worsen magnesium deficiency and contrib-
ute to higher morality [109]. Manganese can
Manganese also become toxic in high quantities and lead to
a manganism, which causes a Parkinson-like ill-
Manganese is a naturally occurring, abundant, ness [110]. Studies of occupation-­related man-
and essential trace element. It operates as a ganese exposure reveal that manganese toxicity
cofactor for many enzymatic reactions involved leads to abnormal ECGs (sinus tachycardia, sinus
with enzymes arginase, pyruvate carboxylase, bradycardia, and arrhythmias), hypertension, and
glutamine synthetase, and manganese superox- hypotension [111]. There are no clinical trials
ide dismutase. It facilitates the metabolism of investigating the impact of manganese on cardio-
cholesterol, some amino acids, and glucose. It is vascular health.
also involved in bone formation and antioxidant
activity such as reactive oxygen species scaveng-
ing [104] and plays a role in homeostasis and the Calcium
clotting cascade (along with vitamin K) [105].
In supplemental forms, manganese is available Calcium is one of the most abundant elements
in differing formulations (bisglycinate chelate, in the human body, with 99% being stored in
glycinate chelate, aspartate, gluconate, picolate, the skeleton [74] and teeth and smaller amounts
citrate, chloride, and sulfate). No current research found inside the cells, in blood and tissues such as
defines the absorption, bioavailability, and toler- the muscle. In addition to its role in bone health,
ance of these different forms; however, iron sta- it is involved with several cellular and tissue
tus appears to affect manganese absorption [106]. functions including muscle contraction, particu-
A small percentage of manganese is absorbed larly vasoconstriction and vasodilation, intracel-
in the small intestines via a known active trans- lular signaling, nerve transmission, and hormonal
port system and a lesser known nonsaturable secretion. In supplementation, calcium exists in
passive mechanism, thought to be facilitated by two main forms: calcium carbonate and calcium
diffusion when intake is high. Most of the man- citrate. Calcium carbonate is more widely avail-
ganese found in the body is present in the bones able and inexpensive but requires stomach acid to
(25–40%), with the remaining amounts stored become bioavailable. In contrast, calcium citrate
in the liver, pancreas, kidney, and brain. Stable is readily absorbed and optimal for individuals
manganese concentrations are maintained in with malabsorptive conditions [112].
the body via a balance of absorption and excre- Once consumed, calcium is absorbed via active
tion [74]. and passive transport in the small intestines [74].
Though research is limited, prospective studies More specifically, the efficiency of calcium is
have identified manganese deficiency as a likely dynamic where absorption increases as the intake
risk factor for ischemic heart disease including level decreases. At low-to-moderate levels, active
coronary artery disease [107]. In a prospective transport occurs and requires the presence of vita-
study, urine manganese had a negative associa- min D. At high intake levels, passive transport
tion [108] with systolic and diastolic blood pres- occurs primarily. This dynamic efficiency is a fea-
sure highlighting cardiovascular association with ture of the mechanism that allows tight regulation
low levels of manganese. Research on the effect of calcium in the body where significant changes
of manganese on heart disease has also looked in intake do not lead to significant changes in con-
at the interplay between manganese and magne- centration unless in severely abnormal states [89]
sium. Manganese and magnesium appear to have that have been long standing.
1 Role of Dietary Nutrition, Vitamins, Nutrients, and Supplements in Cardiovascular Health 9

Calcium is integral to a healthy cardiovascu- proper pH and phosphorylation, a step in the cat-
lar system, particularly with its involvement in alytic activation of proteins. Phosphorus can be
cardiac muscle function. However, calcium sup- obtained in the diet through the consumption of
plementation has been on the rise and evidence a variety of whole foods and dietary supplemen-
from prospective studies [113], RCTs [114], and tation in single and combination formulations,
meta-­analyses [115] suggests that calcium sup- which include MVI. Phosphate additives are also
plement intake is associated with an increased largely present in processed foods. In supplemen-
risk of CVD events and mortality [116]. Though tation, phosphorus is available in the form phos-
concerns have been [116] raised with other stud- phate salts (dipotassium phosphate or disodium
ies [117] showing some conflicting evidence, the phosphate) and phospholipids (phosphatidyl-
most recent meta-analysis [118] continues to sup- choline and phosphatidylserine). Simultaneous
port a concern that calcium supplementation may intake of calcium carbonate and antacids can bind
increase CVD risk. Adverse effects of calcium to phosphorus and prevent its absorption [123].
supplementation seem to occur when total body Once consumed, most phosphorus absorption
calcium is already adequate. A recent review occurs in the jejunum by passive concentration-­
suggests that in spite of the widespread use of dependent processes though some is also
general supplements, there appears to be no evi- absorbed via active transport and the efficiency
dence of significant benefit [19]. There have also of absorption appears to be unaffected by intake
been studies showing a potential benefit of cal- levels. Phosphorus is present in food in the form
cium supplement intake on glucose metabolism of phosphates and phosphate esters. Phosphate is
[119] on lipid levels [120], where calcium binds also stored in the form of phytic acid; however,
to fatty acids leading to decreased absorption in this form requires the presence of the enzyme
the intestines. The current consensus summa- phytase, which is not produced in the human
rized from a recent review [116] appears to be intestines. In the body, phosphorus is primarily
that a more evidence-based approach is needed found in hydroxyapatite (85%), the main com-
and to approach Ca supplementation with cau- ponent of bone and teeth, and to a much lesser
tion as the overall body of evidence is not yet degree in soft tissue (15%).
fully clear. This has not been shown with dietary Many robust studies have outlined an asso-
intake of calcium in observational studies. High ciation with higher serum phosphorus concen-
dietary calcium intake (including food sources trations and CVD as well as CVD mortality in
and supplements) has been associated with lower the CKD and ESRD populations [124, 125],
risk of CVD [121, 122]. The overall recommen- prompting the development of phosphate binders
dation is that use of calcium supplements outside to reduce phosphorus serum levels. The mecha-
of deficiency should be avoided with the encour- nism underlying this includes disordered mineral
agement of dietary intake of calcium. The benefit metabolism associated with impaired kidney
of the use of calcium and vitamin D supplemen- function promoting vascular calcification, arte-
tation remains conflicting and thus unclear. rial stiffness, cardiomyocyte hypertrophy, athero-
sclerosis, and other pathophysiological processes
that impair and damage the cardiovascular sys-
Phosphorus tem [122, 125, 126]. In the general population,
the same association is observed with even mild
Phosphorus is an abundant mineral of critical elevations in serum phosphorus, even at the
importance found naturally in combination with higher end of the normal range [127–131]. Excess
oxygen as phosphate. It is integral to energy dietary phosphorus intake has been commonly
production as a component of ATP and is a key observed in the Westernized population and can
element in the formation of cellular membranes, lead to perturbations in phosphorus homeosta-
nucleic acids, bone, and teeth [74]. Phosphorus sis. Because of the increasing consumption of
is vital to other processes including maintaining processed foods in the American diet, high con-
10 R. Moran et al.

sumption of dietary phosphorus has increasingly of stroke, and increased risk of chronic kidney
become a topic of interest and concern [131]. It disease. Potassium deficiency serves to induce
has been suggested that daily intake of phospho- sodium reabsorption and decrease sodium uri-
rus exceeding 800 mg may have adverse effects nary excretion and decrease vasodilation [136–
[132–134]. Phosphorus restriction has been rec- 138]. One of the benefits derived from potassium
ommended as a strategy to decrease adverse out- intake is its effect on blood pressure where high
comes in the general population. dietary potassium intake has been associated
with decreased blood pressure and subsequently
lower risk of stroke and coronary heart disease.
Potassium Potassium supplementation has been used to
offset the impact of high sodium consump-
Potassium is one of the most important miner- tion. A 2013 systematic review found that high
als found in the body as it serves as one of the potassium intake was associated with a statisti-
main intracellular cations. It is involved in many cally significant decrease in blood pressure in
crucial cellular processes including nerve trans- patients with and without hypertension [137]. A
mission, muscle contraction, vascular tone, and 2011 meta-analysis observed a 21% lower risk
regulation of intracellular and extracellular fluid of stroke with a 1.64-g higher intake of potas-
volume [74]. Potassium can be obtained from sium [138]. Potassium intake was not associated
dietary sources via a wide variety of whole foods with risk of coronary heart disease or risk factors
and dietary supplementation. Forms of potassium associated with it such as blood lipid concentra-
supplementation include potassium chloride (the tions [138].
most commonly used), potassium citrate, phos-
phate aspartate bicarbonate, and gluconate.
Once consumed, potassium is absorbed in the Selenium
small intestines via passive diffusion and con-
centrated in the intracellular and extracellular Selenium is an essential mineral that is found nat-
compartments to create a gradient that drives urally in many foods. It is an integral component
many cellular processes. In a cardiac cell, as of special proteins called selenoproteins that play
in other cells, this gradient is characterized by an important role in thyroid function as cofactors
a high level of potassium inside the cell com- for thyroid hormone deiodinases, reproduction,
pared to outside of the cell, up to 30 times higher DNA synthesis, immune function, redox signal-
in the intracellular space than the extracellular ing, oxidoreductions, and antioxidant activity
space. Enzymatic processes, including sodium– [74, 139]. Selenium has also been identified as
potassium (Na+/K+) ATPase transporter, are playing a role in cell cycle progression and cell
responsible for maintaining this gradient. Other growth and in cancer prevention via the promo-
cellular ions such as Ca and Na have higher tion of cell arrest and induced cell death (apopto-
concentrations outside of the cell. In this state, sis) [140, 141]. Selenium can be obtained from
the cell is polarized as it holds a more negative dietary sources via a wide variety of whole foods
charge inside the cell relative to the outside of and dietary supplementation. In supplementary
the cell. In this state, it is inactive until it depo- forms, selenium is available as selenomethio-
larizes resulting in the phases 0–4 of the action nine, selenium-enriched yeast, sodium selenite,
potential: the rapid upstroke, repolarization, pla- and sodium selenite.
teau, the late repolarization, and diastole [135]. Selenium exists in inorganic (selenate and
Subsequently, the action potential facilitates the selenite) and organic forms (selenomethionine
cellular processes of nerve transmission and and selenocysteine) and is present in human
muscle contraction. tissues in the organic forms. Selenomethionine
A low potassium diet has been associated and selenocysteine are also the dietary forms
with increased blood pressure, increased risk of selenium, with selenomethionine being the
1 Role of Dietary Nutrition, Vitamins, Nutrients, and Supplements in Cardiovascular Health 11

most prominent. Selenate and selenite are not Copper

dietary forms and are used to fortify foods and
in dietary supplements. Both selenomethionine Copper is an essential mineral found naturally
and selenocysteine are well absorbed in the in some foods. It acts as a cofactor for many
GI tract. These four forms of selenium can be enzymes known collectively as cuproenzymes,
ingested and converted to metabolites such as which play an important role as oxidases in the
selenide, which can operate as a precursor for reduction of molecular oxygen. These enzymes
other reactions in the cell, or methylselenol, include diamine oxidase (inactivates the hista-
which is involved in regulation of the cell cycle. mine released in allergic reactions), monoamine
Selenium stores in the body include the skeleton oxidase (plays essential role in the degradation
and the liver. of serotonin and metabolism of catecholamines
Historically, selenium deficiency has been and dopamine), ferroxidases (plays a role in iron
most associated with a juvenile cardiomyopa- transport via ferrous iron oxidation), dopamine,
thy called Keshan disease that is endemic to β-monooxygenase (converts dopamine to norepi-
countries such as China and Eastern Siberia nephrine), and copper/zinc superoxide dismutase
[142, 143]. Though this is a specific dis- (plays a role in antioxidant activity). The activity
ease, the underlying pathology of increased of these enzymes has been shown to decrease with
oxidative stress related to Se deficiency has copper deficiency. Copper also plays an important
been observed in the development of CVD role in angiogenesis, immune system function,
in the general population [144]. The specific regulation of gene expression, neurotransmitter
pathophysiology appears to be related to the homeostasis, and pigmentation [149]. Copper
impaired function of selenoproteins such as can be obtained from dietary sources via a wide
glutathione peroxidase, thioredoxin reductases, variety of whole foods and dietary supplementa-
and methionine sulfoxide reducated B1, which tion. In supplementation, copper exists as cupric
have been specifically linked to cardiovascu- oxide, cupric sulfate, copper amino acid chelates,
lar stress [145]. Mechanisms supporting the and copper gluconate [74].
positive impact of selenium on cardiovascular Copper is primarily absorbed in the small
health include increased antioxidant activity, intestines via saturable-mediated and non-­
reduced apoptosis, and reduced alteration of saturable-­mediated processes and as well as
inflammatory response pathways. The trend energy-dependent transport via Menkes P-type
of adverse CVD risk factors and CVD and its ATPase. Copper absorption is very dependent
association with inadequate mineral levels con- on dietary intake and can vary from 20% to 50%
tinues to be observed with respect to selenium. depending on the milligrams of copper ingested.
However, high selenium exposure in the setting It is mainly bound by ceruloplasmin and trans-
of adequate selenium intake may be associated ported through the body for use and storage in
with increased risks of Type 2 diabetes, lipid cells and specific tissues. Two-thirds of the cop-
levels, and blood pressure as well as adverse per in the body is stored in the skeleton and mus-
cardiometabolic outcomes, though most stud- cle with the remaining third stored in the liver
ies have been cross-­sectional and thus do not where 35% of copper is absorbed in the portal
prove causation. Currently, there is no conclu- vein and delivered to the liver for uptake in the
sive evidence to conclude that use of selenium liver cells [74].
supplements will prevent CVD in nondeficient Cuproenzymes, such as superoxide dismutase
populations [144–148]. This is a needed area of and lysyl oxidase, are crucial for the ­physiological
research as the use of selenium-enriched foods, responses of cardiovascular cells. The expression
supplements, and even fertilizers has notably of cuproenzymes by cardiac cells is tightly regu-
increased in recent years due to increased mar- lated and facilitate angiogenesis, cell growth, cell
keting and consumer interest in selenium’s anti- migration, and wound repair [150]. Deficiency
oxidant capabilities. in this mineral leads to decreased activities of
12 R. Moran et al.

these enzymes leading to pathological mecha- sues. Chromium absorption is found to be quite
nism (peroxidation, glycation, and nitration), low in the body, ranging from 0.5% to 2.5% [74,
resulting in the loss of cell matrix in the heart 157]. Research has suggested that absorption
and blood vessels as well as antioxidant damage may be potentiated by exercise. In the body, chro-
[151–153]. Copper, like many other minerals, has mium stores include the liver, spleen, and bone.
a dual nature where levels that are too high or The impact of chromium on CVD has been
too low are pro-oxidant and are associated with studied within the last two decades but data
disease while sufficient levels allow for normal remain limited. Studies from the 1970s revealed
antioxidant activity and are associated with pre- that chromium was indeed and essential nutrient
vention of disease. In prospective studies, high that played a role in glucose metabolism, particu-
serum copper and ceruloplasmin levels have been larly with insulin, and lipid metabolism [158].
associated with CVD similar to low serum cop- The epidemiological evidence on chromium
per levels [151, 154, 155]. The only randomized intake and CVD is limited but suggests an inverse
trial looking specifically at copper supplement relationship between deficient chromium levels
use found the data to be inconsistent where there [159] and risk of myocardial infarction [160].
was both improvement and worsening of meta- Chromium deficiency has been associated with
bolic markers [156]. hyperglycemia, hyperinsulinemia, insulin resis-
tance, and hypertension, which are all abnormal
physiological states that contribute to type 2 dia-
Chromium betes and metabolic syndrome. In regard to sup-
plementation, some studies have suggested that
Chromium is a trace mineral known to be chromium supplementation improves insulin and
involved in glucose regulation although a com- glucose control [161–163]. There remains a need
prehensive understanding of the role it plays for further research to better understand whether
in human physiology remains to be elucidated chromium supplementation results in cardiovas-
in the research. In addition to playing a role in cular benefit.
glucose regulation by potentiating the action of
insulin, it also appears to be involved with the
metabolism of fats, carbohydrates, and proteins. Macronutrient Supplement
Chromium can be obtained from dietary sources Compounds
as well as dietary supplementation. Chromium
is widely used as a supplement and is present in Macronutrients have also been increasingly eval-
single and combination formulations. It is avail- uated on their role in cardiovascular health. These
able as chromium chloride, chromium nicotinate, compounds—usually taken whole or in combina-
chromium picolinate, high-chromium yeast, and tion with other supplements—have a variety of
chromium citrate [74]. Clarity on which of these impacts in homeostatic function, including mus-
supplemental forms is best to take is limited due cle and myocardial function. Over the last several
to a lack of research. decades, several compounds have been evaluated
Chromium exists in two forms: the dietary including CoA Q10, garlic, pmega-3 fatty acid
form, which is trivalent chromium [74] (chro- oils, resveratrol, red rice yeast, Ginkgo biloba,
mium III), and the form that exists in the envi- and curcumin. In general, compared with vitamin
ronment, hexavalent (chromium VI), which is and elemental supplementation, relatively less is
carcinogenic. The current understanding is that understand about the use of these as supplements.
chromium is absorbed in the small intestines via While some studies have shown promise, the
passive diffusion mechanisms and then trans- complex interplay for much of these compound’s
ported by the protein, transferrin, to various tis- actions remains yet to be elucidated.
1 Role of Dietary Nutrition, Vitamins, Nutrients, and Supplements in Cardiovascular Health 13

CoQ10 tion had been ceased. Reperfusion injury plays

a large part in the long-term consequences of
CoA Q10 (CoQ10) is the only known endog- ischemic heart disease. Due to CoQ10’s mecha-
enous lipid-soluble antioxidant in humans and nism of action both as an antioxidant and as part
is found in high concentrations in the bilipid of the mitochondrial energy machinery, it plays
membranes. Its two primary roles are protect- a valuable role in mitigating the effects of isch-
ing cellular membranes from lipid peroxidation emic injury during and immediately after myo-
by reactive oxygen species and as a carrier in the cardial infarctions. Higher levels of CoQ10 have
electron transport chain [164]. CoQ10 is, unsur- been connected with lower oxidative stress, less
prisingly, found in high concentrations in meta- myocardial necrosis and apoptosis, improved
bolically active tissues such as the heart, liver, cardiac functioning, and increased energy avail-
kidneys, and nervous system [165]. The evidence able directly following a myocardial infarction. A
supporting its role in cardiovascular health is study looking at the correlations of endogenous
mounting, both due to its antioxidant effects and levels of CoQ10 in the blood and the long-term
its role in energy production. The role of inflam- effects of ischemic injury and left ventricular
mation on CVD is well known, and understand- function showed that patients with lower levels
ing the effects of CoQ10 on the heart is important of CoQ10 had worse outcomes than individuals
given the worldwide burden of CVD. with higher levels of CoQ10 6 months after the
Endothelial dysfunction, often caused by reac- event [172]. Due to the time it takes to build up
tive oxygen species (ROS), is found early on in CoQ10 levels in the blood via oral supplementa-
the development of CVD [165]. A meta-analysis tion, acute use after an MI is often too little too
of RCTs looking at CoQ10 supplementation’s late so the therapeutic benefits are seen best when
effects on the vascular flow patterns related to used earlier on in the course of the disease. While
endothelial dysfunction showed that when given the beneficial effects of CoQ10 are seen in the
oral supplementation of CoQ10, there was an early stages of CAD, a meta-analysis of CoQ10
improvement of the flow-mediated dilation of supplementation showed that in heart-failure
the peripheral arteries indicating improvement patients CoQ10 lead to decreased mortality and
of the endothelial dysfunction and the possible improvements in exercise capacity indicating that
therapeutic benefits to the early supplementation it has uses even in secondary prevention [173].
of CoQ10 [166]. This relationship is thought to There is insufficient evidence to support
be mediated by the antioxidant effects of CoQ10 CoQ10 has any effect on hyperlipidemia or blood
and could play a role in both primary and sec- pressure, although preliminary studies suggest it
ondary prevention of CVD [167]. Other studies may play a role in mitigating the effects of hyper-
have shown that CoQ10 supplementation reduces lipidemia on development of atherosclerosis and
inflammatory markers. A case-control study coronary artery disease [174].
looking at CVD and the interplay of reactive Anecdotal evidence suggests that some peo-
oxygen species and CoQ10 showed that cases ple have resolution of statin-induced myopathy
who had had a recent coronary stent placed had with supplementation of CoQ10; however, the
higher levels of oxidative markers and lower lev- evidence supporting this has been mixed. One
els of CoQ10 compared to controls who did not meta-­analysis [175] did show CoQ10 to be
have CVD [168–171]. The long-term effects of beneficial in the muscle weakness, cramps, and
CoQ10 supplementation were studied in a RCT fatigue though not in regards to muscle pain,
among elderly adults who were given CoQ10 and while another meta-analysis [176] found no ben-
selenium supplementation for 4 years. The indi- efit with CoQ10 supplementation in regards to
viduals in the treatment arm had a statistically statin-­induced myopathy. The studies were gen-
significant reduction in mortality that continued erally small with significant heterogeneity mak-
to be seen even 8 years after the supplementa- ing conclusions difficult to assess between trials.
14 R. Moran et al.

Garlic of necrosis [181]. Further studies are needed to

determine how this could lead to a beneficial
Garlic (Allium sativum) has many claims to effect in humans.
health including decreasing lipids, blood pres-
sure, and an antiplatelet effect leading to a risk
reduction of CVD. Allicin, the pungent chemi- Fish Oil
cal that gives garlic its strong flavor, has not been
shown to be absorbed in the gut and is therefore Societies with high amounts of fish in their diets
unlikely responsible for the lauded health effects have been shown to have lower rates of CVD,
of this plant. However, S-allyl-l-cysteine (SAC), raising interest in the use of fish oil supplementa-
a water-soluble organosulfide, found in the aged tion in the prevention of CVD. Fish contains high
garlic formulations, has high bioavailability and levels of polyunsatuated fatty acids (PUFA) with
is thought to be partially responsible for the many a double bond in the third carbon position, more
bioactive effects of garlic. Due to the many dif- commonly known as the omega-3 fatty acids. The
ferent chemicals in garlic, depending on the for- two primary omega-3 FAs are eicosapentaenoic
mulation, it can lead to either no health effects acid (EPA) and docosahexaenoic acid (DHA).
if the primary components are the more vola- The PUFAs have been shown to have multiple
tile chemicals such as allicin, or to significant cardioprotective mechanisms including lower-
improvements in blood pressure and lipid pro- ing of cholesterol and triglycerides, antiarrhyth-
files in formulations containing the more water-­ mic and anti-inflammatory properties [182–185].
soluble SAC components [177]. Studies have shown that supplementation of
In a double-blind placebo-controlled trial, 2–4 g/day leads to a decrease in total cholesterol
researchers found that the use of aged garlic levels in dose dependent manner with or without
extract led to a statistically significant drop in the use of statin medications [186, 187]. Bioactive
blood pressure among participants with uncon- derivatives of the omega-3 FAs have been shown
trolled hypertension. A meta-analysis of 20 RCTs to decrease sudden cardiac death and episodes
showed that garlic supplements lowered both dia- of ventricular tachycardia in patients with recent
stolic and systolic blood pressure [178]. myocardial infarctions [185] making a case for
Not only has garlic been shown to reduce blood its use in secondary prevention. While the data
pressure, it also can lead to a small but significant are mixed on the use of omega-3 FA for primary
reduction in lipid levels. A meta-analysis looking prevention [188–190], recent studies looking at
at clinical trials that used aged black garlic, garlic formulations containing only EPA have shown a
oil, and garlic supplements showed that) garlic clear decrease in the incidence of primary myo-
supplementation led to a significant decrease in cardial infarctions in patients with significant risk
total cholesterol and LDL levels while increasing factors for CVD [191]. Additionally, bioactive
HDL levels [179]. compounds derived from omega-3 have potent
While not as supported as the lipid- and anti-inflammatory properties and are integral to
blood-­pressure-­lowering effects of garlic, prelim- the modulation of the immune system and down-
inary studies have shown garlic supplementation regulation of acute phase reactants. Given the role
has an effect on inhibiting platelet aggregation inflammation plays in CVD, this ability may play
[180] which could prove to be another beneficial a role in the primary prevention of CVD. Thus,
way that garlic is cardioprotective. While there there is great interest in further understanding the
is insufficient evidence on the role garlic plays role of EPA supplementation in average and low-
during acute myocardial infarctions, animal stud- risk individuals.
ies have shown that it protects myocytes from There have been a number of large cohort
hypoxic injury by inducing autophagy instead studies looking at the effects of fish oil on car-
1 Role of Dietary Nutrition, Vitamins, Nutrients, and Supplements in Cardiovascular Health 15

diovascular health which are worth noting. One on whether it is RES alone rather than a combi-
of the difficulties with the use of supplements nation of multiple chemicals in red grapes that
is the unregulated industry, especially amongst explain the “French Paradox” remain.
the over-the-counter (OTC) formulations. The
JELIS trial, which followed 18,645 Japanese
patients and used just the EPA PUFA, and the Red Rice Yeast
REDUCE-IT trial, which followed 8179 cardiac
patients and gave them icosapent ethyl which is a Red Yeast Rice (RYR) has been used in Chinese
highly purified stable form of EPA, both showed medicine as a lipid lowering cardioprotective
improvements in cardiovascular outcomes with supplement for decades. Some formulations of
the use of EPA [176]. However, the VITAL trial, RYR contain high levels of a compound called
which used a fish oil supplement that combined monocolin K, which is chemically identical to
the EPA and DHA [176], showed no significant lovastatin. RYR has been shown to lower LDL-C
cardiovascular benefits. The differences in the comparable to moderate-dose statin medications,
trials demonstrate how the specific components especially in patients who have side effects from
of the supplements can change the outcomes; or prefer not to take statins [193, 194]. RYR has
almost all OTC fish oils are a combination of the been shown to reduce cardiovascular mortality in
EPA and DHA PUFA. Because of this, the cur- patients with diabetes and hypertension in vari-
rent recommendations for the use of nonprescrip- ous clinical trials [195, 196]. One of the concerns
tion (OTC) fish oil supplementation are class III that has been brought up by the FDA is the unreg-
(no benefit) for primary and secondary preven- ulated industry and the amount of monocolin K
tion of CVD [176]. found in various OTC supplements and concerns
over its safety profile given its similarities to
prescription medications [193, 194, 196, 197].
Resveratrol Specific safety concerns are due to the metabo-
lite citrinin. Animal studies have shown neph-
Resveratrol (RES) is a potent antioxidant found rotoxic effects and renal cancer associated with
in the skin of red grapes and is a direct scaven- the chronic use of citrinin. Certain RYR supple-
ger of hydroxyl (•OH) and superoxide (O2•−) ments have been found to have concentrations of
radicals. Given the moderate consumption of red citrinin over the levels recommended safe [195].
wine among the French, it is thought to be one of While studies have clearly shown that RYR with
the chemicals that explains the “French Paradox,” high levels of monocolin K does have similar car-
the observation that low levels of CVD has been dioprotective effects of the statins in both lipid-­
noted among French individuals despite a diet lowering activity and secondary prevention of
rich in saturated fats. Clinical trials in patients cardiac mortality, it can be challenging to know
with CVD have shown that supplementation with what percentage of monocolin K a particular sup-
RES leads to a decrease in platelet aggregation, plement may have.
improved flow mediated dilation, and left ventric-
ular function in patients with recent MI making a
case for its use as a nutraceutical [192]. However, Ginkgo Biloba
questions about bioavailability with oral supple-
mentation, its ability to inhibit CYP3A4, and the One of the most commonly used herbal remedies
lack of significant clinical evidence on the effects in the USA and Europe, Ginkgo biloba is taken
of RES on cardiac health bring into question the with a goal of stabilizing atherosclerotic plaque
efficacy of RES supplementation for primary and and improving blood flow [198]. Ginkgo biloba
secondary prevention of CVD. Further questions has been shown to have anticoagulation proper-
16 R. Moran et al.

ties by direct inhibition of thrombin. Evidence to the anti-inflammatory effects, meta-analyses of

supports that it may decrease early plaque for- RCTs showed that daily use of curcumin reduced
mation in the coronary arteries and stabilizes LDL-C and total cholesterol levels in adults with
existing plaque in CVD patients by downregulat- metabolic syndrome further decreasing cardio-
ing inflammatory markers leading to a decrease vascular risk. Curcumin also has been shown to
in LDL-C oxidation and subsequent foam cell have antiplatelet and anticoagulant properties,
formation [199–201]. While clinical trials are though no trials have been done to show this has
lacking in showing an effect on reduction in mor- a direct effect on cardiac morbidity and mortality
bidity and mortality from cardiovascular events, [203–205]. Overall, curcumin has been shown to
the reduction and stabilization of plaque do indi- be safe and effective in clinical trials [202], and
cate that it may be a useful tool in the prevention thus ongoing trials may provide further evidence
and management of CVD. to support this compound. As it stands, further
research is needed to understand its direct effects
on cardiovascular health.
Curcumin

Curcumin, the active ingredient in turmeric, has Conclusion

long been used in Eastern medicine as a powerful
anti-inflammatory agent. Due to its long history Dietary supplements, vitamins, and minerals
of use, recent studies have sought to understand are a multibillion-dollar industry that makes all
more of what curcumin does in the body. Its sorts of claims about health benefits. While the
primary role in cardiovascular health has to do use of supplements has been found to confer
with its potent anti-inflammatory and antioxidant benefit as evidenced by rigorous studies showing
effects [202]. Curcumin lowers vascular inflam- mortality benefit such as CoQ10 and congestive
mation leading to decreased levels of TNF-a, heart failure, others, such as fish oil, have epi-
IL-6, IL-1, and other inflammatory markers, demiological support but thus far have failed to
which may help to reduce macrovascular compli- show significance of benefit when studied in a
cations, especially among diabetics. In addition systematic way. Table 1.1 outlines an overview

Table 1.1 Summary of supplement dietary sources, common formations, and summary for CVD benefit
Nutrient Dietary source Supplement forms Summary evidence
Multivitamins Varied—whole grains, plant MVI—multivitamins (varied) Dietary intake in foods rich in
sources (legumes, green leafy these vitamins has
vegetables, fruits, nuts); some epidemiological support for CVD
animal sources (meat, such as benefit. Interventional studies
pork, fish, beef) have failed to find consistent
benefit for CVD risk
B Vitamins Varied—whole grains, plant B1—thiamine Supplements of some may lower
sources (legumes, green leafy B3—niacin surrogate markers of CVD risk;
vegetables, fruits, nuts); some B5—pantothenic acid supplements have not consistently
animal sources (meat, such as B6—pyroxidine been found to confer benefit. Diet
pork, fish, beef) B9—folate/folic acid intake in foods rich in these
B12—cyanocobalamin vitamins have epidemiological
support for CVD benefit
Vitamin C Varied fruit sources—citrus, l-ascorbic acid Diets rich in vitamin C have
potatoes, tomatoes; varied inverse associations with incident
vegetable sources including heart disease; supplement use in
potato, broccoli, Brussels isolation has not been found to
sprouts, bell pepper confer CVD risk benefit
1 Role of Dietary Nutrition, Vitamins, Nutrients, and Supplements in Cardiovascular Health 17

Table 1.1 (continued)

Nutrient Dietary source Supplement forms Summary evidence
Vitamin A Animal derived especially Retinol, retinal, and retinyl Carotenoid-rich diets have been
liver; some fish oils; dairy esters; carotenoid compounds orfound to have a lower
products; vegetable sources provitamin A compounds cardiovascular disease risk;
include green leafy (α-carotene, β-carotene, and interventional studies have not
vegetables, tomatoes, potatoes β-cryptoxanthin) found consistent benefit and in
(especially swell potato) some populations (e.g., smokers)
may confer harm
Vitamin D Fatty fish, fish oils; dairy in 25-Hydroxyvitamin D-calcidiol; Epidemiologic support for CVD
particular cheese; egg yolks, 1,25-hydroxyvitamin risk and vitamin D exposure
mushrooms; fortified foods D-calciferol (sun); interventional studies have
such as milk, certain fortified failed to find consistent CVD risk
cereals benefit
Vitamin E Varied—plant sources (green Tocopherols; tocotrienols Largely mixed evidence; large
leafy vegetables, seeds, nuts); intervention trials have not found
some vegetable oils (canola, benefit and possible harm
corn, soybean); some fruits (intracranial bleeds, heart failure
(kiwi, tomato) exacerbations)
Vitamin K Varied—Plant sources (green K1—Phylloquinone Early studies suggest possible
leafy vegetables); some K2—menaquinone benefit of K1 and K2;
vegetable oils; some fruits K3—menadione, derived from interventional studies are ongoing
(blueberries, grapes, K1
pomegranate)
Zinc Whole grains, cashews, Zinc acetate; zinc gluconate Though zinc deficiency has been
sesame seeds, pumpkin seeds, Zinc sulfate implicated in the development of
almonds, chickpeas, legumes, atherosclerosis, current evidence
poultry, beef, lamb, oysters, does not supplementation in
and shrimp primary prevention
Magnesium Green leafy vegetables, Magnesium aspartate; Magnesium supplementation has
legumes, nuts, seeds, whole magnesium chloride; been associated with favorable
grains magnesium citrate; magnesium effects in individuals with CVD
lactate; magnesium oxide risk factors though more research
is needed to elucidate its benefit
in primary prevention
Manganese Plant sources (whole grains, Manganese bisglycinate chelate; Manganese is known more for its
nuts, legumes, leafy manganese glycinate chelate; potential for toxicity. Some
vegetables, coffee, tea, spices manganese aspartate; prospective studies have identified
such as black pepper) and manganese gluconate; an inverse relationship between
animals sources (mollusks) manganese picolate; manganese manganese levels and blood
citrate; manganese chloride; pressure; however, no clinical
manganese sulfate trials have investigated the impact
of manganese on CVD
Calcium Plant sources such as Chinese Calcium carbonate; calcium Studies have provided conflicting
cabbage, kale, and broccoli; citrate evidence on the benefit or adverse
dairy sources such as milk, effects of calcium
yogurt, and cheese; grains supplementation. More studies
when consumed frequently in have suggested an increased risk
adequate amounts of CVD and CVD mortality. Per
most recent guidelines, calcium
supplementation is not
recommended
(continued)
18 R. Moran et al.

Table 1.1 (continued)

Nutrient Dietary source Supplement forms Summary evidence
Phosphorus Plant sources (nuts, legumes, Phosphate salts (dipotassium Excess phosphorus intake is a
vegetables and grains) and phosphate or disodium concern, particularly with the
animal sources (dairy phosphate) phospholipids dietary patent of westernized
products, meats and poultry, (phosphatidylcholine and cultures. Increased intake of
fish and eggs); processed phosphatidylserine) phosphorus has been associated
foods contain phosphate impaired cardiac and renal
additives such as phosphoric function. The overall
acid, sodium phosphate, and recommendation is to decrease
sodium polyphosphate phosphorus intake in the diet
Potassium Plant sources (legumes, green Potassium chloride, potassium Dietary intake associated with
leafy vegetables, fruits, and citrate, potassium phosphate, decreased CVD risk and mortality
nuts) and animal sources potassium aspartate, potassium while supplementation has
(meat, poultry, fish, milk, and bicarbonate, and potassium consistently been found to
yogurt) gluconate decrease blood pressure
Selenium Plant sources (whole grains, Selenomethionine; selenium-­ Currently, there is no conclusive
fruits, vegetables, nuts, enriched yeast; sdium selenite; evidence to conclude that use of
especially Brazil nuts) and sodium selenite selenium supplements will
animal sources (seafood, prevent CVD in nondeficient
meat, and dairy) populations
Copper Plant sources (seeds, nuts, Cupric oxide; cupric sulfate; Both high and low serum copper
grains, chocolate) and animal copper amino acid chelates; and ceruloplasmin levels have
sources (shellfish and organ copper gluconate been associated with CVD in less
meats) robust studies. There are no
clinical trials demonstrating
conclusive evidence on the impact
of copper supplementation on
CVD health
Chromium Whole grains, some fruits Chromium chloride chromium There remains a need for further
(apples, bananas, oranges, and nicotinate; chromium picolinate; research to better understand
grapes), some vegetables high-chromium yeast, chromium whether chromium
(green beans, potatoes, citrate supplementation results in
broccoli, garlic, and basil), and cardiovascular benefit
meats (beef, turkey, chicken)
CoQ10 N/a N/a Cardioprotective against
morbidity and mortality from
ischemic heart disease
Garlic N/a Aged garlic formulations Significant decrease in blood
pressure and small but significant
decreases in LDL-C levels
Fish oil N/a N/a Mixed evidence for cardioprotective
benefits. EPA-only formulations
show cardioprotective benefits.
EPA/DHA OTC formulations do
not show evidence of
cardioprotective benefits
Resveratrol Grapes and red wine N/a Limited evidence on
cardioprotective benefits as a
nutraceutical
Red yeast rice N/a N/a Lowers LDL-C similar to statins.
Concerns over heterogeneity of
active ingredients in supplements
Gingko N/a N/a Anti-inflammatory effects may
biloba lead to stabilization and reduction
of plaque
Curcumin Turmeric N/a Potent anti-inflammatory agent
decreases vascular inflammation
and LDL-C levels
1 Role of Dietary Nutrition, Vitamins, Nutrients, and Supplements in Cardiovascular Health 19

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 Impact of Nutrition on Biomarkers
of Cardiovascular Health
2
Cameron K. Ormiston, Rebecca Ocher,
and Pam R. Taub

Introduction ability of rapid testing. The biomarkers discussed

in this chapter were selected based on their clinical
The role of nutrition and lifestyle as effective strate- relevance and strength of literature available. This
gies to decrease diabetes and cardiovascular disease chapter will focus on how biomarkers can be used
risk is becoming increasingly important as over to assess the impact of diet and lifestyle changes on
one-third of Americans are prediabetic and more cardiovascular health (Fig. 2.1).
than 60% of Americans eat more than the daily
recommended amount of sodium, added sugar,
and saturated fats [1, 2]. Although a wide variety BMI/Body Composition
of diet and lifestyle treatment options are avail-
able to patients, clinical dietary counseling often Obesity, defined by a BMI of greater than 30 kg/
fails to meet patient needs and provide sufficient m2, is a well-known risk factor for dyslipidemia,
guidance and feedback on progress [3]. One way to hypertension, diabetes, cardiometabolic syn-
understand the impact of diet is through biomark- drome, CVD, and cancer. However, extending
ers, which serve as noninvasive, cost-effective, and beyond a pure weight-based assessment, new evi-
diverse tools for physicians to quantify a patient’s dence sheds light on the importance of body fat
responses to nutritional therapy. While there are distribution and body composition in overall health
several methods of monitoring a patient’s response [4, 5]. Numerous tools are available to clinicians
to nutritional therapy, biomarkers are preferred due to quantify body composition. For example, dual
to their low cost, greater accessibility, and avail- energy absorptiometry (DEXA) scans are used to
analyze body composition and are an important
diagnostic tool for osteopenia and osteoporosis.
Further, DEXA scans have been utilized to assess
fat mass normalized by height squared (FMI),
which is advantageous over BMI in that the value
C. K. Ormiston · P. R. Taub (*) is independent of lean muscle mass, and FMI may
Division of Cardiovascular Medicine, Department of be used as a predictor for cardiovascular health [6].
Medicine, University of California San Diego, DEXA scans have been used in clinical research
San Diego, CA, USA
e-mail: [email protected]; [email protected]
and in special populations such as athletes [7].
However, current guidelines suggest that the clini-
R. Ocher
Department of Medicine, University of California, cal utility of DEXA scans in metabolic syndrome
Los Angeles, Los Angeles, CA, USA evaluation requires further research [8].

© Springer Nature Switzerland AG 2021 29

M. J. Wilkinson et al. (eds.), Prevention and Treatment of Cardiovascular Disease, Contemporary
Cardiology, https://doi.org/10.1007/978-3-030-78177-4_2
30 C. K. Ormiston et al.

Achieving Balance

The Benefits and Risks of each Food Group

Fruits and
Proteins Vegetables Grains
Benefits Risks Benefits Risks Benefits Risks
• Increased vitamin D • Red meat: • Increased folate and Mg • Increased risk of • Unrefined grains: • Paleo diet increase
and B12 levels Increases TMAO levels vitamin B12 deficiency Fiber, B vitamin, and TMAO levels
• Lower risk levels • Anti-inflammatory in plant-based eaters mineral source • Weight gain
of hypoalbuminemia Causes leaky gut • Improved microbiome • Reduced zinc Antioxidant effects Refined grains:
• Satiting effects Increased hsCRP diversity and inhibits (negatively affects Improve heart health Promote insulin
• Build and repair tissues Increased CVD risk TMAO synthesis albumin/prealbumin Better weight and resistance
synthesis) glucose control
• Provide energy and • Elevated cholesterol • Reduced LDL Increase hs CRP
maintain muscle • Weight gain • HbA1c regulation • Improved digestion

Fats Dairy
Benefits Risks Benefits Risks
• Unsaturated fats: • Saturated fats: • Increased vitamin D, • Significant source
Increased HDL Increased CVD risk B12, and other bad cholesterol
Reduced LDL Pro-inflammatory essential vitamins and • Dairy rich in saturated
minerals fat increase CVD risk
Increased vitamin D Increased LDL,
• Satiating effects triglycerides • Protein source
Weight gain • Bone health

Fig. 2.1 The effects of each major food group on cardiovascular biomarkers reviewed in this chapter

An even less invasive measurement of body is evidence to suggest that even in women with
composition is the waist-to-hip ratio, measured normal weight, central obesity is associated with
simply by circumference. An increased waist- increased risk of mortality, similar to mortality in
to-­hip ratio shows a significant association with women with elevated BMI with central obesity
risk of myocardial infarction, as well as coro- [14]. These findings underscore the importance of
nary artery disease, and T2D [9], [10]. In fact, assessing not only BMI as a risk factor for future
waist-­to-­hip ratio shows both a graded and a sig- cardiovascular disease, but also central obesity.
nificant association with myocardial infarction, Studies have shown when body composition
especially in comparison to BMI, across ethnic is modified with modalities such as high intensity
groups [11]. The population-attributable risks of exercise and diet, there is a reduction in body fat,
MI for waist-to-hip ratio in the top two quintiles waist circumference and increase in muscle mass.
of INTERHEART study participants was 24.3% For example, patients with a history of myo-
compared with only 7.7% for the top two quin- cardial infarction (n = 90) who performed high
tiles of BMI [9]. The importance of waist-to-hip intensity exercise lost 4 pounds more of body fat,
ratio and waist circumference in predicting car- gained 1.5 pounds more of muscle, and reduced
diometabolic risk has been increasingly recog- their waist circumference by 2.54 cm more than
nized in the literature, and qualitative descriptors those who solely performed moderate exercise
known as “pear” body shaped and “apple” body [15]. In addition, the Mediterranean diet (MD) in
have been applied to describe patients with more particular can be useful in reducing weight cir-
weight around the hips and more weight around cumference, as demonstrated in a meta-analysis
the waist, respectively [12, 13]. Furthermore, there by Kastorini et al. [16].
2 Impact of Nutrition on Biomarkers of Cardiovascular Health 31

Blood Pressure smallest reductions in blood pressure, possibly

due to the fact that more exercise was performed
Numerous large-scale studies have provided at a lower intensity [21]. There are many differ-
strong and consistent evidence that both systolic ent effective options for exercise to reduce blood
(SBP) and diastolic (DBP) blood pressures are pressure, but it may be worthwhile to consider
positively associated with cardiovascular disease prescribing a supervised facility-based exercise
outcomes [17]. These findings are consistent program for patients new to exercise, as this does
across genders, various age groups, racial and yield the highest adherence [21].
ethnic groups, and across different countries. Not
only is elevated blood pressure an overall pre-
dictor for cardiovascular outcomes, systolic and Total Cholesterol
diastolic values are helpful in differentiating risk
for patients and may act as a marker to assess Total cholesterol, a commonly performed mea-
risk of cardiometabolic syndrome [17]. While sure, is the sum of LDL cholesterol, VLDL
hypertension significantly affects the heart, it has cholesterol, HDL cholesterol, intermediate-
multi-­organ effects and is a risk factor for kidney density lipoprotein (IDL) cholesterol and cho-
disease and stroke [18]. lesterol associated with lipoprotein(a) (Lp(a)).
Vegetarians have been shown to have lower Cholesterol is a requirement for physiological
blood pressure than those who eat omnivorous function—it is an essential structural component
diets. In a meta-analysis of 258 studies, vegetar- of cell membranes and acts as a precursor for ste-
ian diets were found to reduce SBP ~5–7 mm Hg roid hormones produced by the body. While the
and DBP by ~2–5 mm Hg, which is equivalent liver’s synthesis of cholesterol is largely deter-
to the effect of losing 2.5 lbs [19]. Mirroring mined by genetic factors and feedback mecha-
these findings , the MD decreases both SBP nisms, the remainder of cholesterol is obtained
(−2.35 mm Hg) and DBP (−1.58 mm Hg) blood through dietary intake. Foods such as dairy
pressure [16]. Conversely, salty foods increase products, eggs, meat, and poultry are significant
risk of hypertension: increasing SBP by 4.58 mm sources of cholesterol in the diet. Though reduc-
Hg and DBP by 2.25 mm Hg per 1000 mg of ing such animal product intake seems intuitive
sodium [20]. Alarmingly, the risk of hyperten- to lower total cholesterol in patients with hyper-
sion for participants in the upper third and fourth lipidemia, dietary cholesterol has little effect on
quartile (>3819 mg/day) is more than 4x higher cardiovascular disease risk [22]. In fact, the rela-
compared to those in the lower two quartiles tionship between dietary cholesterol and cardio-
(P < 0.01). vascular disease is different in a given individual;
Exercise also plays a crucial role in manag- studies demonstrate that the fractional absorption
ing hypertension. Endurance training, dynamic rate of dietary cholesterol is variable, ranging
resistance training and isometric training lower from 20% to 80% [22].
both SBP and DBP [21]. A systematic review According to US population studies, an
and meta-analysis by Cornelissen and Smart in optimal total cholesterol level in an adult is
2013 found that blood pressure reductions after <150 mg/dL [23]. It is important to note, how-
low-­intensity endurance exercise were smaller ever, that there is a large difference in cardiovas-
than blood pressure reductions after moderate- or cular mortality rates for a given total cholesterol
high-intensity training [21]. (Low-intensity exer- value [24]. Total serum cholesterol may be
cise training was defined by <55% of heart rate tracked longitudinally as a way to assess both
maximum or < 40% of heart rate reserve) [21]. risk for cardiovascular disease and nutrition sta-
Surprisingly, this same meta-analysis found that tus, alongside other clinically significant values,
the groups exercising >210 min a week had the discussed below.
32 C. K. Ormiston et al.

Low-Density Lipoproteins (LDL) sclerotic cardiovascular disease and patients

with an LDL >190 mg/dL have a high risk
While total cholesterol is an important value to of atherosclerotic cardiovascular disease
track over time and is a predictor of cardiovas- [23]. LDL is an important value in the clini-
cular risk, LDL is colloquially termed “bad cho- cal assessment of risk for heart disease, and
lesterol” and is the main target of lipid lowering clinicians target therapies based on changes
therapies such as statins. LDL is particularly in LDL, which acts as a useful biomarker.
utilized clinically as epidemiologic data dem- Pharmacologic therapies used to lower LDL
onstrates a positive and consistent relationship include statins, ezetimibe, bile acid seques-
between LDL concentration and cardiovascu- trants, and PCSK9 inhibitors [23].
lar mortality and cardiovascular events. There
is also substantial data to support the effort of
lowering LDL, as reduction decreases patients’ High-Density Lipoproteins (HDL)
cardiovascular risk across a wide spectrum of
patients, including those with known cardiovas- Opposite of LDL, HDL is often introduced to
cular disease. patients as the “good cholesterol.” And unlike
LDL is known to play a key role in the patho- LDL, there is a known inverse relationship
physiology of atherosclerosis. Portions of blood between HDL and the risk for cardiovascular
vessels that are susceptible to atherosclerosis events [28]. HDL is a scavenger of cholesterol––
retain lipoproteins like LDL, and it is this reten- it assists in facilitating the return of cholesterol
tion that is an initial and key step in the forma- from the blood vessels back to the liver for even-
tion of atherosclerotic plaques in the arteries. The tual elimination. Furthermore, HDL prevents
mechanism of plaque formation is well under- oxidation of LDL to limit LDL’s role in the gen-
stood, and the evidence for LDL’s key role in eration of atherosclerotic plaque and prevents
atherosclerotic formation is corroborated by the secretion of the vasoconstrictor endothelin [29].
understanding of Familial Hypercholesterolemia, HDL values <40 mg/dL are considered an
an inherited disease associated with severely ele- independent risk factor for cardiovascular dis-
vated LDL levels and premature atherosclerotic ease [30]. Although low HDL is correlated with
cardiovascular disease [25]. cardiovascular disease, raising HDL by pharma-
While LDL is the target of pharmacotherapy, cologic interventions has not been consistently
diet plays a vital role in LDL reduction. The MD, shown to have significant clinical benefit [31].
which contains large amounts of plant sterols Some diets, such as the MD, have been shown to
and nuts, lowers LDL, as compared to a low-fat increase HDL levels, but the maximum thresh-
controlled diet [26]. Meta-analyses of vegetarian old of improvement appears to be as low as 12%.
diets corroborate that vegetarian diets not only Importantly, saturated fats and, to a lesser extent,
lower total cholesterol, but LDL as well [27]. unsaturated fatty acids have been shown to
Further, nuts such as almonds, hazelnuts, and increase HDL [32]. Moderate alcohol consump-
walnuts have been linked with a decrease in LDL tion, specifically wine, is positively associated
and C-reactive protein, an acute phase reactant with higher levels of HDL [33, 34]. Conversely,
discussed later in this chapter. Additionally, vis- diets high in carbohydrates and low in fats have
cous fiber has been shown to reduce LDL by trap- been associated with low HDL [35]. There is pre-
ping bile salts and preventing reuptake in the GI liminary evidence that aerobic exercise improves
tract, as well as interfering with cholesterol being the anti-inflammatory and anti-oxidative proper-
absorbed into cells [26]. ties of HDL, but the lack of consistent findings
Target LDL is based on multiple factors, in this regard warrants more studies to determine
but US population studies suggest that LDL the importance of exercise on HDL values and
<100 mg/dL manifests in low levels of athero- function [31].
2 Impact of Nutrition on Biomarkers of Cardiovascular Health 33

Non-HDL Cholesterol ther corroborated the strong association between

raised triglycerides and coronary artery disease,
The sum of LDL and VLDL values is termed as well as risk of myocardial infarction and all-­
non-HDL cholesterol , which is more atherogenic cause mortality [42, 43]. In addition to cardiovas-
than LDL or VLDL alone [23]. Therefore, non-­ cular risk, a triglyceride level > 150 mg/dL is a
HDL more accurately assesses atherogenic lip- significant risk factor for metabolic syndrome, a
ids and CV risk than LDL, especially in patients cluster of pathological processes related to insu-
with hypertriglyceridemia. In patients with high lin resistance and elevated free fatty acids [44].
triglycerides, such as patients with metabolic Additionally, elevated triglyceride concentra-
syndrome and Type II Diabetes, LDL is less tions (>885 mg/dL) are associated with risk of
accurately estimated by means of the Friedewald pancreatitis [45].
equation [23, 25]. Due to the limitations of the While these correlations between hypertri-
Friedewald equation, other ways of estimating glyceridemia and risk for cardiovascular disease
LDL have been developed such as the Martin-­ have been well studied, there is a need to further
Hopkins equation, which is a novel method to evaluate the clinical significance of lowering tri-
estimate LDL by using an adjustable factor of glycerides by pharmacotherapy [45]. However,
triglycerides to VLDL ratio [36]. Given that triglycerides are highly affected by diet and life-
there are atherogenic lipids beyond LDL, some style. The MD, high in MUFA, PUFA and dietary
evidence suggests non-HDL cholesterol values fiber, can be particularly helpful in lowering tri-
could be more predictive of cardiovascular risk glycerides [44]. Many studies have shown that
than LDL [37, 38]. In a recent 10-year risk cohort high intake of carbohydrates (greater than 60% of
study, both LDL and non-HDL cholesterol values caloric intake) is associated with a rise in triglyc-
above 160 mg/dL were independently associated erides [44]. In addition, high alcohol consump-
with a 50–80% increased relative risk of mortal- tion is associated with elevated triglycerides, but
ity [39]. low and moderate alcohol intake are associated
In addition to underscoring the importance of with lower triglycerides; this is likely dependent
non-HDL cholesterol as a marker of atheroge- on the type of alcohol consumed [46].
nicity, the 2018 cholesterol management guide- There are several classes of pharmacologic
lines also underscore apolipoprotein B (apoB), agents, such as fibrates, that reduce triglyceride
the major apolipoprotein embedded in LDL and levels, but both weight loss and moderate inten-
VLDL, as a stronger indicator of atherogenicity sity exercise, such as brisk walking and social
than LDL [23]. Another atherogenic biomarker dancing, have been identified as key interventions
similar in clinical utility and risk assessment to to reduce triglyceride levels [47]. Additionally,
apoB is LDL particle number [40]. Both apoB dietary supplementation of ω-3 acid ethyl esters
and LDL particle number have been shown to be can be considered as an additional therapy for
stronger cardiovascular disease risk factors than hypertriglyceridemia with a very minimal side
LDL cholesterol, but apoB has been the prefer- effect profile [48]. Icospaent ethyl, a prescription
able particle for guideline adoption given lower highly purified eicosapentaenoic acid, has been
cost, standardization, and scalability [40]. shown to lower triglycerides and reduce the risk
of ischemic cardiac events [49].

Triglycerides
Lipoprotein(a)
Meta-analyses have demonstrated that both ele-
vated fasting and non-fasting triglycerides are Lp(a) is a well-known risk factor for coronary
associated with increased risk of coronary artery disease that is highly heritable; elevated levels
disease [41]. The Women’s Health Study fur- are associated with atherosclerosis development
34 C. K. Ormiston et al.

and incidence of cardiovascular events [50]. Study suggests hs-CRP predicts cardiovascular
Specifically, elevated Lp(a) levels have been events even in groups that have no other apparent
associated with both coronary disease and cal- markers of cardiovascular disease [58]. An hs-
cific aortic valve disease. Lp(a) is distinguished CRP <2.0 mg/L is often considered the threshold
from LDL by the presence of apolipoprotein for low risk and a value of >2.0 mg/L is consid-
(a), which likely mediates proinflammatory and ered the threshold for higher risk [59].
prothrombotic effects of the protein [51]. While Provided that inflammation plays a key role
Lp(a) is a modified LDL particle, Lp(a) levels in the pathophysiology of atherosclerotic for-
are independent of LDL levels [25]. There is sig- mation, the correlation between hs-CRP and
nificant evidence to support the use of Lp(a) as cardiovascular disease is not surprising. Even in
a risk factor for CVD, and there are randomized patients with low levels of atherogenic biomark-
trials ongoing that are targeting Lp(a) [52, 53]. ers such as non-HDL cholesterol and apoB, a
It is important to note that treatment with nia- discordantly elevated hs-CRP level resulted in
cin can reduce Lp(a) up to 20–30% but has not a 30–60% greater relative risk of developing
been associated with improved outcomes [25]. ASCVD compared to patients with low hs-CRP
Interestingly, monoclonal antibodies to PCSK9 [59]. While many cardiovascular risk factors
may lower Lp(a) by 30% and have been associ- such as smoking, diabetes, and hypertension can
ated with improved outcomes in large clinical increase the inflammatory response and, thereby,
trials such as FOURIER and ODESSEY [25, hs-CRP, an anti-inflammatory diet may be help-
54, 55]. Additionally, there are new pharmaco- ful in reducing systemic inflammation and could
logic approaches in phase III clinical trials that help improve cardiovascular outcomes. Anti-­
target Lp(a) lowering and it will be important to inflammatory diets are the subject of many stud-
assess if lowering Lp (a) translates to decreased ies currently, but it has been well established
CV events [53]. There are little data available to that ω-3 fatty acids are anti-inflammatory, and
support the influence of dietary choices on lower- ω-6 fatty acids tend to be pro-inflammatory.
ing Lp(a), but several studies suggest that low-fat ω-3 fatty acids may be found in walnuts, canola
diets may result in an increase in Lp(a) [56]. oil, and soybean oil, and fish such as salmon,
halibut, and mackerel. Conversely, ω-6 acids are
found in corn and sunflower oils. It is generally
Hs-CRP recommended that protein in an anti-inflamma-
tory diet be plant-based with small amounts of
C-reactive protein (CRP), produced by the liver, fish and lean meats. Further, the phytonutrients
is a marker of systemic inflammation [57]. found in soy-based proteins have been dem-
High-­sensitivity C-reactive protein (hs-CRP) onstrated to have anti-inflammatory properties
is a higher sensitivity test that can detect lower [60]. While a comprehensive anti-inflamma-
grades of inflammation than a standard CRP test tory diet is beyond the scope of this text, the
[57]. While numerous pathologic processes rang- Mediterranean and other plant-based diets have
ing from infection to autoimmune disease can been identified as general guidelines with anti-
elevate hs-CRP levels, it can also be used as a inflammatory properties.
global assessment of cardiovascular risk. Given
that many processes can lead to systemic inflam-
mation, hs-CRP elevations may be transient in  MAO and the Gut Microbiome
T
response to infection and should be repeated (Fig. 2.2)
when these confounding processes are quies-
cent. Meta-analysis conducted by Li et al. sug- Trimethylamine N-oxide is a gut microbiota-­
gests hs-­CRP can stratify cardiovascular risk and dependent biomarker derived from L-carnitine,
all-cause mortality risk in the general population choline, and betaine. TMAO levels reflect a
[57]. Further, data from the Women’s Health pro-­
atherogenic milieu in the gut microbi-
2 Impact of Nutrition on Biomarkers of Cardiovascular Health 35

Higher TMAO Leaky gut

Increased
Inflammation
(hsCRP)

• Fiber increased lactic acid bacteria

(ie: Ruminococcus and E. rectale)

• Polyphenols from plant foods like soy

increase Bifidobacterium and Lactobacillus

Plant based diet Animal based diet

Decreased risk for Increased risk for
cardiovascular disease cardiovascular disease

Fig. 2.2 The impacts of a plant-based diet vs. animal-based diet on TMAO levels, the gut microbiome, and the risk of
coronary arterial plaque buildup. (Printed with permission from ©Christina Pecora)

ome and is associated with poor CV outcomes with TMAO levels >3.98 μmol/L ate more than
[61]. The n­ormal range for serum TMAO is the daily recommended amount of red meat per
0.5–5 μmol/L. TMAO is felt to play a role in day [62].
cardiovascular disease and enhancing CV risk. Conversely, plant-based diets can decrease
A study on adults undergoing elective diagnos- TMAO levels by promoting more diverse and
tic cardiac catheterization found that partici- stable microbiota. This is due to greater intake
pants who had a major cardiac event ≤3 years of fiber, polyphenols, and beneficial bacteria.
of catheterization had higher baseline TMAO For example, Klimenko et al. found plant-based
levels compared to those who did not experience diets greatly improve microbiome diversity [63].
a cardiac event (5.0 μM vs. 3.5 μM; P < 0.001). Long-term fruit and vegetable consumption also
Furthermore, elevated levels of TMAO were improved local microbial diversity (p < 0.05).
associated with a significant risk of mortality Moreover, reduced meat and greater fruit/veg-
(hazard ratio (HR): 3.37; P < 0.001) and non- etable consumption can be cardioprotective and
fatal myocardial infarction/stroke (HR: 2.135; inhibit TMAO production. In Koeth et al.’s study
P < 0.001) [61]. on L-carnitine metabolism, omnivores produced
Foods rich in phosphatidylcholine (beef, eggs, >20× more plasma TMAO than vegans despite
and pork) get converted into trimethylamine and consuming the same amount of L-carnitine
then TMAO. Increased choline levels induce (p = 0.001) [64].
greater gut microbial activity and, subsequently The MD has also shown to promote gut diver-
higher levels of TMAO. The KarMeN study, sity and reduce TMAO levels. De Filippis et al.
which monitored plasma TMAO levels in healthy examined the relationship between MD adherence
adults after eating red meat, found a positive cor- and gut microbiota, observing significantly lower
relation (r = 0.25) between red meat consump- urinary TMAO levels in plant-based eaters vs.
tion and choline levels. Additionally, participants omnivores (p < 0.0001) and MD adherence hav-
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 IX.
Pinocchio vende l'Abbecedario per andare a vedere il teatro
dei burattini.

Smesso che fu di nevicare, Pinocchio, col suo bravo Abbecedario

nuovo sotto il braccio, prese la strada che menava alla scuola: e
strada facendo, fantasticava nel suo cervellino mille ragionamenti e
mille castelli in aria, uno più bello dell'altro.
E discorrendo da sè solo, diceva:
— Oggi, alla scuola, voglio subito imparare a leggere: domani poi
imparerò a scrivere, e domani l'altro imparerò a fare i numeri. Poi,
colla mia abilità, guadagnerò molti quattrini e coi primi quattrini che
mi verranno in tasca, voglio subito fare al mio babbo una bella
casacca di panno. Ma che dico di panno? Gliela voglio fare tutta
d'argento e d'oro, e coi bottoni di brillanti. E quel pover'uomo se la
merita davvero; perchè insomma, per comprarmi i libri e per farmi
istruire, è rimasto in maniche di camicia.... a questi freddi! Non ci
sono che i babbi che sieno capaci di certi sacrifizi!... —
Mentre tutto commosso diceva così, gli parve di sentire in
lontananza una musica di pifferi e di colpi di grancassa: pì-pì—pì, pì-
pì—pì, zum, zum, zum, zum.
Si fermò e stette in ascolto. Quei suoni venivano di fondo a una
lunghissima strada traversa, che conduceva a un piccolo paesetto,
fabbricato sulla spiaggia del mare.
 — Che cosa sia questa musica? Peccato che io debba andare a
scuola, se no.... —
E rimase lì perplesso. A ogni modo, bisognava prendere una
risoluzione; o a scuola, o a sentire i pifferi.
— Oggi anderò a sentire i pifferi, e domani a scuola. Per andare a
scuola c'è sempre tempo — disse finalmente quel monello, facendo
una spallucciata.
Detto fatto, infilò giù per la strada traversa e cominciò a correre a
gambe. Più correva e più sentiva distinto il suono dei pifferi e dei
tonfi della grancassa: pì-pì—pì, pì—pì-pì, pì-pì—pì, zum, zum, zum,
zum.
Quand'ecco che si trovò in mezzo a una piazza tutta piena di
gente, la quale si affollava intorno a un gran baraccone di legno e di
tela dipinta di mille colori.
— Che cos'è quel baraccone? — domandò Pinocchio, voltandosi a
un ragazzetto che era lì del paese.
— Leggi il cartello, che c'è scritto, e lo saprai.
— Lo leggerei volentieri, ma per l'appunto oggi non so leggere.
— Bravo bue! Allora te lo leggerò io. Sappi dunque che in quel
cartello a lettere rosse come il fuoco, c'è scritto: Gran Teatro dei
Burattini....
— È molto che è incominciata la commedia?
— Comincia ora.
— E quanto si spende per entrare?
— Quattro soldi. —
Pinocchio che aveva addosso la febbre della curiosità, perse ogni
ritegno e disse, senza vergognarsi, al ragazzetto col quale parlava:
— Mi daresti quattro soldi fino a domani?
 — Te li darei volentieri, — gli rispose l'altro canzonandolo — ma
oggi per l'appunto non te li posso dare.
— Per quattro soldi ti vendo la mia giacchetta — gli disse allora il
burattino.
— Che vuoi che mi faccia di una giacchetta di carta fiorita? Se ci
piove su, non c'è più verso di cavarsela da dosso.
— Vuoi comprare le mie scarpe?
— Sono buone per accendere il fuoco.
— Quanto mi dai del berretto?
— Bell'acquisto davvero! Un berretto di midolla di pane! C'è il
caso che i topi me lo vengano a mangiare in capo! —

— Vuoi darmi quattro soldi di quest'Abbecedario nuovo?

Pinocchio era sulle spine. Stava lì lì per fare l'ultima offerta: ma

non aveva coraggio: esitava, tentennava, pativa. Alla fine disse:
— Vuoi darmi quattro soldi di quest'Abbecedario nuovo?
 — Io sono un ragazzo e non compro nulla dai ragazzi — gli
rispose il suo piccolo interlocutore, che aveva più giudizio di lui.
— Per quattro soldi l'Abbecedario lo prendo io — gridò un
rivenditore di panni usati, che s'era trovato presente alla
conversazione.
E il libro fu venduto lì su due piedi. E pensare che quel
pover'uomo di Geppetto era rimasto a casa, a tremare dal freddo in
maniche di camicia, per comprare l'Abbecedario al figliuolo!
 X.
I burattini riconoscono il loro fratello Pinocchio e gli fanno una
grandissima festa; ma sul più bello esce fuori il burattinaio
Mangiafoco, e Pinocchio corre pericolo di fare una brutta fine.

Quando Pinocchio entrò nel teatrino delle marionette, accadde un

fatto che destò una mezza rivoluzione.
Bisogna sapere che il sipario era tirato su, e la commedia era già
incominciata.
Sulla scena si vedevano Arlecchino e Pulcinella, che bisticciavano
fra di loro e, secondo il solito, minacciavano da un momento all'altro
di scambiarsi un carico di schiaffi e di bastonate.
La platea tutta attenta, si mandava a male dalle grandi risate, nel
sentire il battibecco di quei due burattini, che gestivano e si
trattavano d'ogni vitupero con tanta verità, come se fossero proprio
due animali ragionevoli e due persone di questo mondo.
Quando all'improvviso, che è che non è, Arlecchino smette di
recitare, e voltandosi verso il pubblico e accennando colla mano
qualcuno in fondo alla platea, comincia a urlare in tono drammatico:
— Numi del firmamento! sogno o son desto? Eppure quello
laggiù è Pinocchio!...
— È Pinocchio davvero! — grida Pulcinella.
 .... Eppure quello laggiù è Pinocchio!...

— È proprio lui! — strilla la signora Rosaura, facendo capolino in

fondo alla scena.
— È Pinocchio! è Pinocchio! — urlarono in coro tutti i burattini,
uscendo a salti fuori delle quinte.
— È Pinocchio! È il nostro fratello Pinocchio! Evviva Pinocchio!...
— Pinocchio, vieni quassù da me! — grida Arlecchino — vieni a
gettarti fra le braccia dei tuoi fratelli di legno! —
A questo affettuoso invito, Pinocchio spicca un salto, e di fondo
alla platea va nei posti distinti; poi con un altro salto, dai posti
distinti monta sulla testa del direttore d'orchestra, e di lì schizza sul
palcoscenico.
È impossibile figurarsi gli abbracciamenti, gli strizzoni di collo, i
pizzicotti dell'amicizia e le zuccate della vera e sincera fratellanza,
che Pinocchio ricevè in mezzo a tanto arruffio degli attori e delle
attrici di quella compagnia drammatico-vegetale.
 Questo spettacolo era commovente, non c'è che dire: ma il
pubblico della platea, vedendo che la commedia non andava più
avanti, s'impazientì e prese a gridare: — Vogliamo la commedia!
vogliamo la commedia! —
Tutto fiato buttato via, perchè i burattini, invece di continuare la
recita, raddoppiarono il chiasso e le grida, e, postosi Pinocchio sulle
spalle, se lo portarono in trionfo ai lumi della ribalta.
Allora uscì fuori il burattinaio, un omone così brutto, che metteva
paura soltanto a guardarlo. Aveva una barbaccia nera come uno
scarabocchio d'inchiostro, e tanto lunga, che gli scendeva dal mento
fino a terra: basta dire che, quando camminava se la pestava coi
piedi. La sua bocca era larga come un forno, i suoi occhi parevano
due lanterne di vetro rosso, col lume acceso di dietro; e con le mani
schioccava una grossa frusta, fatta di serpenti e di code di volpe
attorcigliate insieme.
 All'apparizione inaspettata del burattinaio, ammutolirono tutti.

All'apparizione inaspettata del burattinaio, ammutolirono tutti:

nessuno fiatò più. Si sarebbe sentito volare una mosca. Quei poveri
burattini, maschi e femmine, tremavano come tante foglie.
— Perchè sei venuto a mettere lo scompiglio nel mio teatro? —
domandò il burattinaio a Pinocchio, con un vocione d'Orco
gravemente infreddato di testa.
— La creda, illustrissimo, che la colpa non è stata mia!...
— Basta così! stasera faremo i nostri conti. —
Difatti, finita la recita della commedia, il burattinaio andò in
cucina, dov'egli s'era preparato per cena un bel montone, che girava
lentamente infilato nello spiede. E perchè gli mancavano le legna per
finirlo di cuocere e di rosolare, chiamò Arlecchino e Pulcinella e disse
loro:
 — Portatemi di qua quel burattino, che troverete attaccato al
chiodo. Mi pare un burattino fatto di un legname molto asciutto, e
sono sicuro che a buttarlo sul fuoco, mi darà una bellissima
fiammata all'arrosto. —
Arlecchino e Pulcinella da principio esitarono; ma impauriti da
un'occhiataccia del loro padrone, obbedirono: e dopo tornarono in
cucina portando sulle braccia il povero Pinocchio, il quale,
divincolandosi come un'anguilla fuori dell'acqua, strillava
disperatamente: — Babbo mio, salvatemi! Non voglio morire, no,
non voglio morire!... —
 XI.
Mangiafoco starnutisce e perdona a Pinocchio, il quale poi
difende dalla morte il suo amico Arlecchino.

Il burattinaio Mangiafoco (che questo era il suo nome) pareva un

uomo spaventoso, non dico di no, specie con quella sua barbaccia
nera che, a uso grembiale, gli copriva tutto il petto e tutte le gambe;
ma nel fondo poi non era un cattiv'uomo. Prova ne sia, che quando
vide portarsi davanti quel povero Pinocchio, che si dibatteva per ogni
verso, urlando «Non voglio morire, non voglio morire!» principiò
subito a commuoversi e a impietosirsi; e dopo aver resistito un bel
pezzo, alla fine non ne potè più, e lasciò andare un sonorosissimo
starnuto.
A quello starnuto, Arlecchino che fino allora era stato afflitto e
ripiegato come un salcio piangente, si fece tutto allegro in viso, e
chinatosi verso Pinocchio gli bisbigliò sottovoce:
— Buone nuove, fratello! Il burattinaio ha starnutito, e questo è
segno che s'è mosso a compassione per te, e oramai sei salvo. —
Perchè bisogna sapere che, mentre tutti gli uomini quando si
sentono impietositi per qualcuno, o piangono, o per lo meno fanno
finta di rasciugarsi gli occhi, Mangiafoco, invece, ogni volta che
s'inteneriva davvero, aveva il vizio di starnutire. Era un modo come
un altro, per dare a conoscere agli altri la sensibilità del suo cuore.
 Dopo avere starnutito, il burattinaio, seguitando a fare il burbero,
gridò a Pinocchio:
— Finiscila di piangere! I tuoi lamenti mi hanno messo
un'uggiolina qui in fondo allo stomaco.... sento uno spasimo, che
quasi quasi.... etcì, etcì! — e fece altri due starnuti.
— Felicità! — disse Pinocchio.
— Grazie. E il tuo babbo e la tua mamma sono sempre vivi? —
domandò Mangiafoco.
— Il babbo, sì; la mamma non l'ho mai conosciuta.
— Chi lo sa che dispiacere sarebbe per il tuo vecchio padre, se
ora ti facessi gettare fra quei carboni ardenti. Povero vecchio! lo
compatisco.... etcì, etcì, etcì, — e fece altri tre starnuti.
— Felicità! — disse Pinocchio.
— Grazie. Del resto bisogna compatire anche me, perchè come
vedi, non ho più legna per finire di cuocere quel montone arrosto, e
tu, dico la verità, in questo caso mi avresti fatto un gran comodo! Ma
ormai mi sono impietosito e ci vuol pazienza. Invece di te, metterò a
bruciare sotto lo spiede qualche burattino della mia compagnia. Olà,
giandarmi! —
A questo comando comparvero subito due giandarmi di legno,
lunghi lunghi, secchi secchi, col cappello a lucerna in testa e colla
sciabola sfoderata in mano.
 — Pigliatemi lì quell'Arlecchino....

Allora il burattinaio disse loro con voce rantolosa:

— Pigliatemi lì quell'Arlecchino, legatelo ben bene, e poi gettatelo
a bruciare sul fuoco. Io voglio che il mio montone sia arrostito
bene! —
Figuratevi il povero Arlecchino! Fu tanto il suo spavento, che le
gambe gli si ripiegarono e cadde bocconi per terra.
Pinocchio alla vista di quello spettacolo straziante, andò a gettarsi
ai piedi del burattinaio, e piangendo dirottamente e bagnandogli di
lacrime tutti i peli della lunghissima barba, cominciò a dire con voce
supplichevole:
— Pietà, signor Mangiafoco!...
 — Qui non ci sono signori! — replicò duramente il burattinaio.
— Pietà, signor Cavaliere!...
— Qui non ci sono cavalieri!
— Pietà, signor Commendatore!
— Qui non ci sono commendatori!
— Pietà, Eccellenza!... —
A sentirsi chiamare Eccellenza, il burattinaio fece subito il
bocchino tondo, e diventato tutt'a un tratto più umano e più
trattabile, disse a Pinocchio:
— Ebbene, che cosa vuoi da me?
— Vi domando grazia per il povero Arlecchino!...
— Qui non c'è grazia che tenga. Se ho risparmiato te, bisogna
che faccia mettere sul fuoco lui, perchè io voglio che il mio montone
sia arrostito bene.
— In questo caso — gridò fieramente Pinocchio, rizzandosi e
gettando via il suo berretto di midolla di pane — in questo caso
conosco qual è il mio dovere. Avanti, signori giandarmi! Legatemi e
gettatemi là fra quelle fiamme. No, non è giusta che il povero
Arlecchino, il vero amico mio, debba morire per me! —
Queste parole, pronunziate con voce alta e con accento eroico,
fecero piangere tutti i burattini che erano presenti a quella scena. Gli
stessi giandarmi, sebbene fossero di legno, piangevano come due
agnellini di latte.
Mangiafoco, sul principio, rimase duro e immobile come un pezzo
di ghiaccio: ma poi, adagio adagio, cominciò anche lui a
commuoversi e a starnutire. E fatti quattro o cinque starnuti, aprì
affettuosamente le braccia e disse a Pinocchio:
 — Tu sei un gran bravo ragazzo! Vieni qua da me, e dammi un
bacio. —
Pinocchio corse subito, e arrampicandosi come uno scoiattolo su
per la barba del burattinaio, andò a posargli un bellissimo bacio sulla
punta del naso.
— Dunque la grazia è fatta? — domandò il povero Arlecchino, con
un fil di voce che si sentiva appena.
 E arrampicandosi come uno scoiattolo su per la barba del burattinaio....

— La grazia è fatta! — rispose Mangiafoco; poi soggiunse

sospirando e tentennando il capo:
— Pazienza! per questa sera mi rassegnerò a mangiare il
montone mezzo crudo: ma un'altra volta, guai a chi toccherà!... —

Alla notizia della grazia ottenuta, i burattini corsero tutti sul

palcoscenico e, accesi i lumi e i lampadari come in serata di gala,
cominciarono a saltare e a ballare.
Era l'alba e ballavano sempre.
 XII.
Il burattinaio Mangiafoco regala cinque monete d'oro a
Pinocchio perchè le porti al suo babbo Geppetto: e Pinocchio,
invece, si lascia abbindolare dalla Volpe e dal Gatto e se ne va
con loro.

Il giorno dipoi Mangiafoco chiamò in disparte Pinocchio e gli

domandò:
— Come si chiama tuo padre?
— Geppetto.
— E che mestiere fa?
— Il povero.
— Guadagna molto?
— Guadagna tanto quanto ci vuole per non aver mai un
centesimo in tasca. Si figuri che per comprarmi l'Abbecedario della
scuola dovè vendere l'unica casacca che aveva addosso: una casacca
che, fra toppe e rimendi, era tutta una piaga.
— Povero diavolo! Mi fa quasi compassione. Ecco qui cinque
monete d'oro. Va' subito a portargliele, e salutalo tanto da parte
mia. —
Pinocchio, come è facile immaginarselo, ringraziò mille volte il
burattinaio: abbracciò, a uno a uno, tutti i burattini della compagnia,
anche i giandarmi; e fuori di sè dalla contentezza, si mise in viaggio
per ritornarsene a casa sua.
 — Com'è che sai il mio nome?

Ma non aveva fatto ancora mezzo chilometro, che incontrò per la

strada una Volpe zoppa da un piede e un Gatto cieco da tutt'e due
gli occhi, che se ne andavano là là, aiutandosi fra di loro, da buoni
compagni di sventura. La Volpe, che era zoppa, camminava
appoggiandosi al Gatto: e il Gatto, che era cieco, si lasciava guidare
dalla Volpe.
— Buon giorno, Pinocchio, — gli disse la Volpe, salutandolo
garbatamente.
— Com'è che sai il mio nome? — domandò il burattino.
— Conosco bene il tuo babbo.
— Dove l'hai veduto?
— L'ho veduto ieri sulla porta di casa sua.
— E che cosa faceva?
— Era in maniche di camicia e tremava dal freddo.
 — Povero babbo! Ma, se Dio vuole, da oggi in poi non tremerà
più!
— Perchè?
— Perchè io sono diventato un gran signore.
— Un gran signore tu? — disse la Volpe, e cominciò a ridere di un
riso sguaiato e canzonatore: e il Gatto rideva anche lui, ma per non
darlo a vedere, si pettinava i baffi colle zampine davanti.
— C'è poco da ridere — gridò Pinocchio impermalito. — Mi
dispiace davvero di farvi venire l'acquolina in bocca, ma queste qui,
se ve ne intendete, sono cinque bellissime monete d'oro. —
E tirò fuori le monete avute in regalo da Mangiafoco.
Al simpatico suono di quelle monete, la Volpe per un moto
involontario allungò la gamba che pareva rattrappita, e il Gatto
spalancò tutt'e due gli occhi, che parvero due lanterne verdi; ma poi
li richiuse subito, tant'è vero che Pinocchio non si accòrse di nulla.
— E ora — gli domandò la Volpe — che cosa vuoi farne di
codeste monete?
— Prima di tutto — rispose il burattino — voglio comprare per il
mio babbo una bella casacca nuova, tutta d'oro e d'argento, e coi
bottoni di brillanti: e poi voglio comprare un Abbecedario per me.
— Per te?
— Davvero: perchè voglio andare a scuola e mettermi a studiare
a buono.
— Guarda me! — disse la Volpe. — Per la passione sciocca di
studiare ho perduto una gamba.
— Guarda me! — disse il Gatto. — Per la passione sciocca di
studiare ho perduto la vista di tutt'e due gli occhi. —
 In quel mentre un Merlo bianco, che se ne stava appollaiato sulla
siepe della strada, fece il suo solito verso e disse:
— Pinocchio, non dar retta ai consigli dei cattivi compagni: se no,
te ne pentirai! —
Povero Merlo, non l'avesse mai detto! Il Gatto spiccando un gran
salto, gli si avventò addosso, e senza dargli nemmeno il tempo di
dire ohi, se lo mangiò in un boccone con le penne e tutto.
Mangiato che l'ebbe e ripulitosi la bocca, chiuse gli occhi daccapo
e ricominciò a fare il cieco come prima.
— Povero Merlo! — disse Pinocchio al Gatto — perchè l'hai
trattato così male?

Spiccando un gran salto, gli si avventò addosso.

— Ho fatto per dargli una lezione. Così un'altra volta imparerà a

non metter bocca nei discorsi degli altri. —
 Erano giunti più che a mezza strada, quando la Volpe, fermandosi
di punto in bianco, disse al burattino:
— Vuoi tu raddoppiare le tue monete d'oro?
— Cioè?
— Vuoi tu, di cinque miserabili zecchini, farne cento, mille,
duemila?
— Magari! e la maniera?
— La maniera è facilissima. Invece di tornartene a casa tua,
dovresti venir con noi.
— E dove mi volete condurre?
— Nel paese dei Barbagianni. —
Pinocchio ci pensò un poco, e poi disse risolutamente:
— No, non ci voglio venire. Oramai sono vicino a casa, e voglio
andarmene a casa, dove c'è il mio babbo che m'aspetta. Chi lo sa,
povero vecchio, quanto ha sospirato ieri, a non vedermi tornare.
Purtroppo io sono stato un figliuolo cattivo, e il Grillo-parlante aveva
ragione quando diceva: «I ragazzi disobbedienti non possono aver
bene in questo mondo.» Ed io l'ho provato a mie spese, perchè mi
sono capitate molte disgrazie, e anche ieri sera in casa di Mangiafoco
ho corso pericolo.... Brrr! mi viene i bordoni soltanto a pensarci!
— Dunque, — disse la Volpe — vuoi proprio andare a casa tua?
Allora va' pure, e tanto peggio per te.
— Tanto peggio per te! — ripetè il Gatto.
— Pensaci bene, Pinocchio, perchè tu dai un calcio alla fortuna.
— Alla fortuna! — ripetè il Gatto.
— I tuoi cinque zecchini, dall'oggi al domani sarebbero diventati
duemila.
— Duemila! — ripetè il Gatto.
 — Ma com'è mai possibile che diventino tanti? — domandò
Pinocchio, restando a bocca aperta dallo stupore.
— Te lo spiego subito; — disse la Volpe — bisogna sapere che nel
paese dei Barbagianni c'è un campo benedetto chiamato da tutti il
Campo dei miracoli. Tu fai in questo campo una piccola buca e ci
metti dentro, per esempio, uno zecchino d'oro. Poi ricoprì la buca
con un po' di terra: l'annaffi con due secchie d'acqua di fontana, ci
getti sopra una presa di sale, e la sera te ne vai tranquillamente a
letto. Intanto, durante la notte, lo zecchino germoglia e fiorisce, e la
mattina dopo di levata, ritornando nel campo, che cosa trovi? Trovi
un bell'albero carico di tanti zecchini d'oro quanti chicchi di grano
può avere una bella spiga nel mese di giugno.
— Sicchè dunque — disse Pinocchio sempre più sbalordito — se
io sotterrassi in quel campo i miei cinque zecchini, la mattina dopo
quanti zecchini vi troverei?
— È un conto facilissimo; — rispose la Volpe — un conto che puoi
farlo sulla punta delle dita. Poni che ogni zecchino ti faccia un
grappolo di cinquecento zecchini: moltiplica il cinquecento per
cinque, e la mattina dopo trovi in tasca duemilacinquecento zecchini
lampanti e sonanti.
— Oh che bella cosa! — gridò Pinocchio, ballando dall'allegrezza.
— Appena che questi zecchini li avrò raccolti, ne prenderò per me
duemila e gli altri cinquecento di più li darò in regalo a voialtri due.
— Un regalo a noi? — gridò la Volpe sdegnandosi e chiamandosi
offesa. — Dio te ne liberi!
— Te ne liberi! — ripetè il Gatto.
— Noi — riprese la Volpe — non lavoriamo per il vile interesse:
noi lavoriamo per arricchire gli altri.
 — Gli altri! — ripetè il Gatto.
— Che brave persone! — pensò dentro di sè Pinocchio: e
dimenticandosi lì sul tamburo, del suo babbo, della casacca nuova,
dell'Abbecedario e di tutti i buoni proponimenti fatti, disse alla Volpe
e al Gatto:
— Andiamo subito, io vengo con voi. —
 XIII.
L'osteria del «Gambero Rosso.»

Cammina, cammina, cammina, alla fine sul far della sera

arrivarono stanchi morti all'osteria del Gambero Rosso.
— Fermiamoci un po' qui, — disse la Volpe — tanto per mangiare
un boccone e per riposarci qualche ora. A mezzanotte poi
ripartiremo, per essere domani, all'alba, nel Campo dei miracoli. —
Entrati nell'osteria si posero tutt'e tre a tavola: ma nessuno di
loro aveva appetito.
Il povero Gatto, sentendosi gravemente indisposto di stomaco,
non potè mangiare altro che trentacinque triglie con salsa di
pomodoro e quattro porzioni di trippa alla parmigiana: e perchè la
trippa non gli pareva condita abbastanza, si rifece tre volte a
chiedere il burro e il formaggio grattato!
La Volpe avrebbe spelluzzicato volentieri qualche cosa anche lei:
ma siccome il medico le aveva ordinato una grandissima dieta, così
dovè contentarsi di una semplice lepre dolce e forte, con un
leggerissimo contorno di pollastre ingrassate e di galletti di primo
canto. Dopo la lepre si fece portare per tornagusto un cibreino di
pernici, di starne, di conigli, di ranocchi, di lucertole e d'uva
paradisa; e poi non volle altro.
 Quello che mangiò meno di tutti fu Pinocchio.

Aveva tanta nausea per il cibo, diceva lei, che non poteva
accostarsi nulla alla bocca.
Quello che mangiò meno di tutti fu Pinocchio. Chiese uno
spicchio di noce e un cantuccio di pane e lasciò nel piatto ogni cosa.
Il povero figliuolo, col pensiero sempre fisso al Campo dei miracoli,
aveva preso un'indigestione anticipata di monete d'oro.
Quand'ebbero cenato, la Volpe disse all'oste:
— Datemi due buone camere, una per il signor Pinocchio e
un'altra per me e per il mio compagno. Prima di ripartire stiacceremo
un sonnellino. Ricordatevi, però, che a mezzanotte vogliamo essere
svegliati per continuare il nostro viaggio.
— Sissignore — rispose l'oste, e strizzò l'occhio alla Volpe e al
Gatto, come dire: «Ho mangiato la foglia e ci siamo intesi!...» —